Skip to main content

Shedding light on the phenotypic–genotypic correlation of rare treatable and potentially treatable pediatric movement disorders



Advances in genetic science have led to the identification of many rare treatable pediatric movements disorders (MDs). We explored the phenotypic–genotypic spectrum of pediatric patients presenting with MDs. By this, we aimed at raising awareness about such rare disorders, especially in our region. Over the past 3 years, we reviewed the demographic data, clinical profile, molecular genetics and other diagnostic workups of pediatric patients presenting with MDs.


Twelve patients were identified; however, only six patients were genetically confirmed. The phenomenology of MDs ranged from paroxysmal kinesigenic choreoathetosis (1 patient), exercise-induced dyskinesia (2 patients), ataxia (2 patients) and dystonia (2 patients). Whole-exome sequencing in addition to the functional studies for some patients revealed a specific genetic diagnosis being responsible for their MDs. The genetic diagnosis of our patients included infantile convulsions and paroxysmal choreoathetosis syndrome and episodic ataxia due to “pathogenic homozygous mutation of PRRT2 gene,” glucose transporter type 1 deficiency-exercise induced dyskinesia due to “De Novo pathogenic heterozygous missense mutation of exon 4 of SLC2A1 gene,” aromatic L amino acid decarboxylase deficiency due to “pathogenic homozygous mutation of the DDC gene,” myopathy with extrapyramidal signs due to “likely pathogenic homozygous mutations of the MICU1 gene,” mitochondrial trifunctional protein deficiency due to “homozygous variant of uncertain significance (VUS) of HADHB gene” and glutaric aciduria II with serine deficiency due to “homozygous VUS for both ETFDH and PHGDH genes.” After receiving the treatment as per recognized treatment protocols, two patients showed complete resolution of symptoms and the rest showed variable responses.


Identifying the genetic etiology of our patients guided us to provide either disease-specific treatment or redirected our management plan. Hence, highlighting the value of molecular genetic analysis to avoid the diagnostic odyssey and identify treatable MDs.


Pediatric movement disorders (MDs) are a large group of heterogeneous neurological disorders presenting during childhood until adolescence [1]. Several factors sometimes render the diagnosis quite challenging in this age group. Some of these factors are related to overlapping or variable phenotypes even within the same family. Phenotypic variability is mainly due to variable penetrance and/or variable expressivity of the same mutation [2]. Other factors could be related to age-related variability in the phenotypic presentation [1], lack of expertise [3], rarity of some disorders [4] and limited resources for diagnostic genetic analysis in our region [5].

Generally, there are three groups of MDs identified: hyperkinetic and hypokinetic MDs and ataxia. Hyperkinetic MDs also called "dyskinesias” such as dystonia, chorea and myoclonus are prevailing among the pediatric age group, whereas hypokinetic disorders such as Parkinson's disease are prevailing in adults [6]. Ataxia is neither a hyper- nor a hypokinetic MDs rather it is the inability to perform a well-coordinated voluntary movement that cannot be explained by muscle weakness or involuntary movements [7]. Noteworthy to mention is that pediatric MDs can also be paroxysmal due to episodes of neurological dysfunction that are either isolated or part of a more complex disorder. Paroxysmal MDs include both paroxysmal dyskinesia, consisting of attacks of dystonic and/or choreic movements, and episodic ataxia (EA), characterized by attacks of cerebellar ataxia [8].

Owing to the revolution in genetic science in the past two decades, various genetic etiologies of inherited MDs have been identified resulting in better understanding of genotype–phenotype correlations. This has led to better knowledge about specific treatments, dietary modifications, avoidance of certain triggers and enzyme replacement therapy [4]. This implies an urgent need for early recognition of the underlying etiology aimed at modifying the disease course rather than providing symptomatic treatment.

In this study, we will review and analyze the clinical and genetic profile as well as the treatment response among pediatric patients diagnosed at our clinic with rare genetic treatable and potentially treatable MDs. By this, we aim to offer a better understanding among pediatricians and child neurologists of phenotypic variability to ensure early diagnosis and avoid the diagnostic odyssey with other neurological disorders.


Ethical approval and patient screening

The ethical approval for this study was granted by the Institutional Review Board at the American Center for Psychiatry and Neurology in Abu Dhabi, UAE. All activities were carried out with ICH GCP compliance. The patients were screened during the period of February 2018 to February 2021. Pediatric patients presenting with possible MDs, exercise intolerance, muscle pain/cramps or abnormal gait were evaluated by taking a detailed history and undergoing a thorough neurological examination. Once patients were identified as having possible MD, the caregivers were counseled about the possible genetic diagnosis and the required genetic test.

An informed consent form was signed by the patients’ caregivers. Blood samples for whole-exome sequencing (WES) were collected using the CentoCard (Centogene AG, Germany) following the standard protocol.

Clinical investigation

The demographic data including gender, age at “onset of symptoms, presentation and last visit,” ethnicity, mode of delivery, parental consanguinity, perinatal and family history were reviewed for all the patients who were identified with pathogenic, likely pathogenic or variant of uncertain significance (VUS) in the WES analysis. We analyzed the phenotypic presentation of the MD in terms of onset, duration, frequency, triggering factors, associated symptoms and signs. Other comorbidities such as “recurrent chest infections, speech delay, feeding and intellectual difficulties” and effects on ambulation were described. In the diagnostic workup biochemical studies, electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) findings were included.

Biochemical analysis and WES

Double-stranded DNA capture baits against approximately 36.5 Mb of the human coding exome (targeting > 98% of the coding reference sequence and Gencode v28 regions, which was obtained from the human genome build GRCh37/hg19 on May 2018) were used to enrich target regions from fragmented genomic DNA with the Twist Human Core Exome Plus kit. The generated library was sequenced on an Illumina platform to obtain at least 20 × coverage depth for > 98% of the targeted bases. The bioinformatics pipeline included read alignment to GRCh37/hg19 genome assembly, variant calling and annotation, and comprehensive variant filtering. All disease-causing variants reported in HGMD®, in ClinVar and in CentoMD® as well as all variants with minor allele frequency (MAF) below 1% in the gnomAD database are considered. The investigation for relevant variants is focused on coding exons and flanking ± 20 intronic bases.

Additional tests

Additional functional tests were performed for three of our patients whose WES showed VUS to determine the likelihood of the pathogenic or benign nature of their variants. This was applied in the following patients:

  • Patient 3, the functional enzymatic activity of L-amino decarboxylase enzyme.

  • Patient 4, functional studies included western blot on cultured fibroblast for a MICU1 protein product. Moreover, measurement of the respiratory chain enzymes, Complex V and the reference enzymes citrate synthetase was done for functional analysis of NDUFAF6 gene activity.

  • Patient 6, measurement of cerebrospinal fluid (CSF) and blood serine level and in silico analysis of glutaric acid protein for functional study of products of both PHGDH and ETFDH genes, respectively.

The received diagnosis and treatment before presentation were described. Finally, the treatment received after confirming the genetic diagnosis and its effect on clinical outcome was highlighted.


Twelve patients were identified to have possible MDs during the study period. Blood samples for WES were collected from six patients. One male patient was treated based on the genetic diagnosis of his elder brother with complete resolution of symptoms (patient 1). The rest of our patients could not proceed with WES for personal reasons.

All our six patients who were enrolled in the study were born via spontaneous vaginal delivery (SVD) with an uneventful perinatal course and good Apgar score except for patient 3. All patients were from the Middle East. All parents were 1st degree cousins except patient 2. Detailed patient demographic data and comorbidities are listed in Table 1. The phenomenology of MDs ranged from paroxysmal kinesigenic choreoathetosis (PKC) (1 patient), exercise-induced dyskinesia (2 patients), ataxia (2 patients) and dystonia (2 patients). Two patients presented with seizures (patient 1 and 6). Further phenomenology details, triggering factors, clinical features and course are described in Table 2.

Table 1 Patient’s demographic data and comorbidities
Table 2 Patient’s phenomenology, clinical features and course

Clinical presentation and the diagnostic work

Patient 1: A 5-year-old boy who presented with 3 different types of events- seizures during infancy, EA at the age of 1 year and PKC a combination of “dystonic/choreoathetotic” movements at the age of 3 years. The genetic diagnosis of infantile convulsions and paroxysmal choreoathetosis (ICCA) syndrome and EA were confirmed based on WES analysis which revealed a pathogenic homozygous mutation of PRRT2 gene (c.880-34G>A: p.(?)). His younger brother had PKC at the age of 14 months; however, parents did not want to proceed with further genetic testing. Both siblings were prescribed a low dose of carbamazepine with complete resolution of symptoms. The elder brother had learning difficulties. Otherwise, both parents and the elder sister were asymptomatic.

Patient 2: A 9-year-old girl who presented with recurring events of weakness and inability to walk. They were initially infrequent (once/a few times per month) but later became more frequent (once per week) after swimming classes. Reportedly, at the age of 3 and 9 months, she had paroxysmal eye movements that lasted for a few seconds and subsided on their own. Her WES analysis showed De Novo pathogenic heterozygous missense mutation of exon 4 of SLC2A1 gene (c.457c>T; pArg153Cys) confirming the diagnosis of glucose transporter type 1 (GLUT-1) deficiency-exercise induced dyskinesia. Her symptoms were resolved by a modified Atkins diet but she will become symptomatic whenever she is off ketosis.

Patient 3: An 18-month old boy who was initially diagnosed with cerebral palsy and epilepsy secondary to hypoxic-ischemic brain injury. He was born at 39 weeks, SVD, Apgar score was 5, 7 and 8 at 1, 5 and 10 min, respectively. He was admitted to the NICU for 2 weeks due to respiratory difficulties and hypotension (mean BP 40–45 mmHg). He was noted to have less eye-opening and normal neurological examination. Soon after discharge, he had recurrent daily events of facial dystonia and whole body dystonic posturing. His WES analysis showed pathogenic homozygous mutation of the DDC gene (c.242C>T; p.Pro81Leu). Additional functional measurement of aromatic L-amino acid decarboxylase (AADC) activity in the plasma showed low enzymatic activity which confirmed the diagnosis of Aromatic L-amino acid decarboxylase (AADC) deficiency according to the consensus guidelines diagnostic recommendations [9], as shown in Tables 3 and 4. His autonomic symptoms, disturbed sleep pattern, agitation and dystonic crisis showed remarkable improvement after receiving treatment but he was still profoundly delayed as shown in Table 5.

Table 3 Patient’s diagnostic work up, previously received diagnosis and treatment
Table 4 Patient’s final diagnosis and phenotypic/genotypic correlation
Table 5 Treatment, response and outcome after confirmed genetic diagnosis:

Patient 4: A 13-year-old boy who was previously healthy except for a history of febrile seizures during infancy. He presented with walking difficulties at the age of 5 years. He was diagnosed with possible hereditary spastic paraplegia. At the age of 12 years, he developed sudden dystonic posturing with loss of balance and falling triggered by emotional excitement. His elder brother had severe spasticity and ichthyosis for which he was investigated for possible Söjgren Larsson syndrome, but the results were normal.

His WES analysis detected likely pathogenic homozygous mutations of the MICU1 gene (c.553C>T; p.Gin185) and a VUS of NDUFAF6 genes (c.808C>G; p.Leu270Val). The result of WES was matched with a diagnosis of myopathy with extrapyramidal signs (MPXPS) caused by a variant detected in the MICU1 gene. However, to rule out a contribution of NDUFAF6 variant to the phenotype of the patient, additional respiratory chain functional evaluation and western blot assessment were performed for NDUFAF6 and MICU1 gene products, respectively, in cultured fibroblasts. Activities of respiratory chain enzymes, Complex V and the reference enzymes citrate synthetase in cultured fibroblasts showed normal activities. These results made it unlikely that the NDUFAF6 variant that has been identified in our patient to be pathogenic. On the other hand, western blot experiments on fibroblast of the patient to assess the expression levels of the MICU1 protein showed that there was reduced expression of the protein in the patient cells, in comparison with the levels in control cells.

Patient 5: A 16-year-old boy who had an acute generalized weakness with bulbar dysfunction following a febrile illness at the age of 6 years. He was suspected to have Guillain–Barre syndrome versus myasthenia gravis. He was given intravenous immunoglobulins and was finally treated as a case of immune-mediated myasthenic syndrome. His symptoms including weakness even without exertion, walking difficulties, dysphagia and recurrent chest infections persisted even while receiving pyridostigmine. So, treatment was discontinued. Later on, his symptoms were limited to exercise-induced muscle weakness, cramps and pain. He was investigated at our clinic at the age of 15 years and was genetically confirmed to have mitochondrial trifunctional protein deficiency (MTP) caused by homozygous VUS of HADHB gene (c.397A>G; p.Thr133Ala).

Patient 6: A 3-year-old girl who had a positive neonatal screening for glutaric aciduria II (GA-II) and non-conclusive acylcarnitine test. She did not have any clinical concerns until she had her 1st unprovoked seizure at the age of 25 months with subsequent psychomotor regression. She was also noted to have an unsteady gait with frequent falling and speech difficulties. She was maintained on valproic acid, lamotrigine and clonazepam. She failed to respond to two other antiepileptic drugs (AEDs). At the age of 3 years, she presented at our clinic for a second opinion. Her seizure was described as behavioral arrest, staring with eyelid flutter. The mother reported that valproic acid showed the best seizure control. However, it worsened her gait and balance. At this point, EEG showed very frequent multifocal epileptiform discharges arising independently from either posterior temporo-occipital head region, more on the right side as shown in Fig. 1a, b. The molecular studies for neuronal ceroid lipofuscinosis were requested; however, she was referred to complete her neurometabolic work up at the tertiary hospital metabolic clinic. Her WES analysis revealed homozygous VUS for both ETFDH and PHGDH genes. The patient was confirmed to have GA-II with serine deficiency using biochemical studies and in silico analysis as shown in details in Tables 3 and 4. The patient’s detailed neurometabolic/genetic workup was also published by my colleagues [10], since we shared her clinical care. However, we were keen to share our experience with this joint patient as part of our treatable/potentially treatable MD case series. After receiving the proper treatment protocol and weaning off valproic acid, her seizures were well controlled as shown in Table 5.

Fig. 1
figure 1

Two EEG epochs for patient 6, showing multifocal epileptiform discharges. a Average montage, b bipolar montage

The detailed diagnostic workup carried out during the patient’s journey from the beginning of symptoms till reaching the confirmed genetic diagnosis is displayed in Tables 3 and 4.

After reaching the proper genetic diagnosis of our patients, they were maintained on the universally recognized treatment protocol for such diagnosis. Two patients showed complete resolution of symptoms, one patient showed remarkable improvement and 3 patients showed some symptomatic relief as shown in Table 5.


Here in this study, we analyzed the detailed phenotypic–genotypic relationship in six patients presenting with MDs at our pediatric neurology division. All patients were Arabs. All parents were 1st degree cousins except one, emphasizing the impact of consanguineous marriage on the increased rate of autosomal recessive genetic disorders in our region [11]. All our patients had triggers that either initiated or had worsened their MDs. Two patients had shown some clinical clues that had raised our clinical suspicion for specific MDs such as “paroxysmal eye movements” in patient 2 and “oculogyric crises and hypotonia” in patient 3. Five patients were initially misdiagnosed and three patients were prescribed inappropriate medications.

Patient 1 was diagnosed with ICCA and EA due to a novel homozygous PRRT2 pathogenic variant. PRRT2 encodes a protein that is expressed in the central nervous system (CNS) and is thought to be involved in the modulation of synaptic neurotransmitter release. PRRT2 mutations are associated with a variety of paroxysmal disorders including paroxysmal kinesigenic dyskinesia (PKD), exercise-induced dyskinesia, paroxysmal non-kinesigenic dyskinesia (PNKD) [12], benign familial infantile epilepsy (BFIE), ICCA [13], EA, hemiplegic migraine, intellectual disability and benign paroxysmal torticollis of infancy [14].

ICCA syndrome is a rare neuro-genetic disorder characterized by the association of benign infantile seizures (BIS) during early infancy followed by PKC later in life [13]. EAs are identified by recurrent attacks of cerebellar ataxia lasting for a few seconds up to several days. The most commonly reported causative mutations were detected in the KCNA1 (EA1) and CACNA1A (EA2) genes [8]. Other rare mutations were detected in SCN2A [15], FGF14 [16] and PRRT2 genes [14].

PRRT2 mutations are autosomal dominantly inherited. However, some patients with compound heterozygous and others with homozygous mutations were reported [12, 13]. These patients inherit mutation(s) from both asymptomatic parents, which suggests autosomal recessive (AR) inheritance. In addition, incomplete low penetrance of PRRT2 mutations was reported [13], as evidenced by variable intra-familial expressivity [17]. A similar observation was noted among our patient family members, where both parents and elder sister were asymptomatic, the younger brother had PKC and the elder brother had learning difficulties. It would have been helpful if a genetic analysis was performed to explore variable phenotypic presentation among family members. This warrants particular attention by genetic counselors during counseling families of an affected member.

Genetic analysis of our patient has shown homozygote biallelic splice mutation (c.880-34G>A: p.(?)) leading to an AR inheritance. Similar splicing mutation (c.880-35G>A) of intron 2 was reported in an 18-month-old child presenting with IC, followed by PKD, the mother of whom had PKD only despite having an identical mutation [18]. To our knowledge, our patient is the first to present with both ICCA and EA due to PRRT2 mutation. This additional finding of EA tends to be present in the case of biallelic mutations as reported by Delcourt et al. [19].

Since early infancy, our patient was misdiagnosed and received multiple trials of AEDs. Similar to previous publications [17, 18], our patient and his brother showed complete resolution of symptoms after receiving low dose carbamazepine, highlighting the importance of revising the diagnosis in cases with idiopathic refractory epilepsy.

Patient 2 was diagnosed with GLUT-1 deficiency-exercise induced dyskinesia based on the genetic analysis showing de novo heterozygous missense mutation of exon 4 of SLC2A1 gene (c.457c>T; pArg153Cys) and low glucose level in CSF. Most detected SLC2A1 mutations are “de novo” as in our case. In familial cases, inheritance is autosomal dominant mainly with complete penetrance [20]; however, AR inheritance has been less frequently reported [21, 22].

Glucose is the main source of energy for brain metabolism. Glucose transport protein type 1 (GLUT1) facilitates glucose transport across the blood–brain barrier [23]. GLUT1 deficiency syndrome is due to heterozygous mutations in the SLC2A1 gene resulting in failure of delivery of glucose into the brain cells [24]. The amount of reduction of GLUT1 protein will affect the severity of the disease phenotype through the haploinsufficiency mechanism. The higher the amount of the protein produced, the milder the clinical phenotype [22]. The phenotypic spectrum includes developmental delay, seizures, acquired microcephaly and various paroxysmal MDs such as ataxia, dystonia and exercise-induced dyskinesia [20, 24]. Our patient had transient self-limiting paroxysmal eye movements during infancy which is considered one of the earliest clinical features in some patients with GLUT1 deficiency [25]. Later on, she developed exercise-induced dyskinesia during childhood. Our patient responded well to the modified Atkins diet, similar to other studies [24, 26], showing favorable response especially with early diagnosis and initiation of the dietary therapy.

Patient 3 was diagnosed with AADCD due to a pathogenic homozygous mutation of the DDC gene and low AADC enzyme activity in the plasma. Dopamine and serotonin represent the two major monoamine neurotransmitters of the mammalian nervous system [27]. Dopamine is the precursor of norepinephrine and epinephrine [28]. AADC enzyme is the last enzyme involved in the biosynthesis pathway of monoamine neurotransmitters. Therefore, AADC enzyme deficiency will result in severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine leading to a rare AR neurometabolic disorder known as AADCD [29].

AADCD symptoms typically present during the first months of life. The most important characteristic clinical features of AADCD are hypotonia and oculogyric crises. Most patients have severe phenotypic spectrum in the form of early-onset ptosis, hypokinesia, dystonia, impaired development, failure to thrive and autonomic dysfunction [29]. Milder disease course has been described in a few patients [30].

AADCD is caused by mutations in the AADC gene leading to the loss of function of DDC. More than 50 different mutations of the AADC gene have been reported, most of them are substitution mutations. However, deletions, insertions and splice mutations also exist [31]. There are no clear genotype–phenotype correlations except for founder splice mutation(s) of the Far East which are associated with the severe phenotype [32]. On the other hand, most substitution mutations result in abnormal protein configuration inducing a remarkable change of loop 1, 2 or 3 of the enzymes which prevent the acquisition of a fully active form of the enzyme [33]. This is the case of the mutation reported in our patient c.242C>T p.(Pro81Leu) which affects loop 1 of the enzyme (residue 66–84). Core diagnostic keys for AADCD rely on three elements: AADC activity in plasma, typical CSF AADCD pattern and detection of homozygous or compound heterozygous mutations. The presence of two positive elements as in our patient is considered to be diagnostic [9].

Unified evidence-based treatment guidelines are lacking, and treatment protocols vary from one center to another due to the rarity of the condition [27]. Based on the available literature, a consensus guideline for the diagnosis and treatment was proposed in 2017, showing variable outcomes with the use of selective dopamine agonists, monoamine oxidase (MAO) inhibitors, pyridoxine and anticholinergic agents [9]. On receiving treatment, our patient showed partial improvement in severity and frequency of dystonia with fewer crises. Therefore, early diagnosis of this rare neurometabolic disease is essential to provide a better outcome and avoid misdiagnosis requiring unnecessary lifelong treatments such as the use of AEDs. Moreover, an emerging gene therapy through bilateral intraputaminal infusions of adeno-associated virus vector harboring DDC has shown some improvement of motor and cognitive abilities. However, more studies are still required for ensuring safety and efficacy in the long term [34, 35].

Patient 4 was diagnosed with myopathy with extrapyramidal signs (MPXPS) due to homozygous likely pathogenic mutation in the MICU1 gene and reduced expression of MICU1 protein in the fibroblast cells.

Mitochondrial Ca2 + homeostasis is essential for many physiological functions in the neuromuscular system [36]. Physiological Ca2 + level in the mitochondria is required for regulating the aerobic metabolism; on the other hand, Ca2 + overload triggers cell death [37]. Loss of function of MICU1 gene results in defective mitochondrial Ca2 + signaling, mitochondrial fragmentation [36] resulting in brain and muscle disorder [37]. This has been described as MPXPS which is a rare AR mitochondrial disorder due to mutation in the MICU1 gene located on chromosome 10q22.1 [38]. MICU1 protein can be detected in cultured fibroblasts by the western blot technique. The absence of expression of this protein in cultured fibroblasts is an indicator of its functional loss [39]. This was demonstrated in our case by western blot analysis of MICU1 protein on cultured fibroblasts.

MPXPS has variable neuromuscular manifestations including muscle weakness, extrapyramidal motor disorders, developmental delay, impaired cognition, hypertrophied calf muscles, hyperkalemia and cardiomegaly [37, 38, 40, 41]. Different mutations of the MICU1 gene have been reported [37,38,39]. Our patient showed mutation close to that reported by Musa et al. [42], [c.553C>T (p.Q185*)] a middle eastern founder mutation.

Patient 5 was diagnosed with MTP deficiency due to homozygous VUS of the HADHB gene. MTP is a multienzyme complex “formed of four alpha and four beta subunits” which is responsible for catalyzing the final three steps in beta-oxidation of long-chain fatty acids [42]. MTP is encoded by 2 genes, namely “HADHA and HADHB” [43]. Pathogenic variants in the HADHB gene are causative for MTP deficiency, an AR metabolic disorder of mitochondrial fatty acid oxidation [44]. It has diverse clinical manifestations, ranging from a severe lethal neonatal form with cardiomyopathy, hypoketotic hypoglycemia, sudden infant death [45], infantile-onset form with a hepatic Reye-like syndrome [46], late-onset neuromyopathic form with peripheral neuropathy, episodes of rhabdomyolysis [47] to mild myopathy [48, 49]. This phenotypic diversity is related to the defective fatty oxidation pathway, which is the major source of energy for skeletal and cardiac muscles particularly during fasting, physical exertion or stress [50].

Although we detected VUS in the HADHB gene in our patient [c.397A>G p.(Thr133Ala)], his clinical presentation was matching the clinical profile reported in previous publications [48, 49]. There is some evidence suggesting that a strict dietary regimen consisting of low fat, high carbohydrate and medium-chain triglycerides (MCT) supplements might delay long-term cardiac and hepatic complications [44]. Our patient showed mild improvement with better exercise tolerance on dietary regimen and levocarnitine supplement; however, it was difficult to remain compliant.

Patient 6 was diagnosed with serine deficiency and GA-II, based on the detection of two missense homozygous VUS in ETFDH:p.Pro227Thr and PHGDH:p.Ser407Pro. Both variants were detected in a heterozygous state in parents, while only the ETFDH c.679C>A variant was detected in a heterozygous state in her healthy sibling. Therefore, the diagnosis was confirmed based on the patient’s clinical presentation, auxiliary biochemical studies and the favorable response to treatment [10].

Serine deficiency is a rare AR disease caused by deficiency of one of the three enzymes, most commonly the “3-phosphoglycerate dehydrogenase (3-PGDH)” enzyme that is involved in serine metabolism. This will be manifested biochemically by low serine levels in the plasma and CSF [51]. The phenotypic spectrum ranges from a severe lethal form known as “Neu-Laxova syndrome” [52] to a milder form with nonspecific neurodevelopmental delay [53] depending on the residual enzymatic activity [52, 54]. Various neurological presentations have been reported including microcephaly, psychomotor regression, spasticity, seizures [55, 56] and cerebellar ataxia or adult progressive polyneuropathy [51].

GA-II, also known as multiple acyl-CoA dehydrogenase deficiency (MADD), is an AR disease caused by homozygous or compound heterozygous mutations of ETFA, ETFB or ETFDH genes. This will lead to defects in electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH) with a resultant MAD insufficiency [57]. According to the position and nature of the identified variants position and the level of enzymatic activity [58], two forms of GA-II were described. The neonatal-onset severe form presents with or without congenital anomalies, respiratory failure, hypotonia, hypoglycemia and metabolic acidosis [59, 60]. The late-onset milder form presents with myopathic symptoms such as myalgia, muscle weakness and liver dysfunction [61].

Our patient showed an overlapping phenotypic spectrum in the form of muscle weakness, psychomotor regression, ataxia and refractory seizures. Complete cessation of seizures and remarkable improvement in the quality of life was achieved after receiving treatment. Identification of serine deficiency is essentially important knowing that it is a treatable disorder, unlike other neurometabolic disorders. Therefore, the appropriate dose of serine supplementation guided by biochemical correction of serine level is essential for better seizure control as shown in our patient [53].


After analyzing the phenotypic/genotypic spectrum of paroxysmal MDs of our patients, it was evident that early diagnosis is essential to identify treatable and potentially treatable pediatric MDs. Although we had a small number of patients, we were able to appreciate the effect of diagnosis-specific treatment on avoiding unnecessary medications, modifying the course of the disease and improving the quality of life of our patients.

Availability of data and materials

Not applicable.



Aromatic L amino acid decarboxylase deficiency


Benign familial convulsions


Episodic ataxia


Glutaric aciduria type II


Glucose transporter type 1 deficiency


Infantile convulsions and paroxysmal choreoathetosis syndrome


Pediatric movement disorders


Myopathy with extrapyramidal signs


Mitochondrial trifunctional protein deficiency


Not reported


Paroxysmal kinesigenic choreoathetosis


Spontaneous vaginal delivery


Variant of uncertain significance


  1. Galosi S, Nardecchia F, Leuzzi V (2020) Treatable inherited movement disorders in children: spotlight on clinical and biochemical features. Mov Disorders Clin Pract 7(2):154–166

    Google Scholar 

  2. Singer H, Mink J (2015) Movement disorders in childhood. Academic Press

    Google Scholar 

  3. Painous C, Os N, Delamarre A, Michailoviene I, Marti M, Warrenburg B et al (2020) Management of rare movement disorders in Europe: outcome of surveys of the European Reference Network for Rare Neurological Diseases. Eur J Neurol 27(8):1493–1500

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Jinnah H, Albanese A, Bhatia K, Cardoso F, Da Prat G, de Koning T et al (2017) Treatable inherited rare movement disorders. Mov Disord 33(1):21–35

    PubMed  PubMed Central  Google Scholar 

  5. Gatto E, Walker R, Gonzalez C, Cesarini M, Cossu G, Stephen C et al (2021) Worldwide barriers to genetic testing for movement disorders. Eur J Neurol 28(6):1901–1909

    PubMed  Google Scholar 

  6. Schlaggar B, Mink J (2003) Movement disorders in children. Pediatr Rev 24(2):39–51

    PubMed  Google Scholar 

  7. Sanger T, Chen D, Delgado M, Gaebler-Spira D, Hallett M, Mink J (2006) Definition and classification of negative motor signs in childhood. Pediatrics 118(5):2159–2167

    PubMed  Google Scholar 

  8. Méneret A, Roze E (2016) Paroxysmal movement disorders: an update. Rev Neurol 172(8–9):433–445

    PubMed  Google Scholar 

  9. Wassenberg T, Molero-Luis M, Jeltsch K, Hoffmann G, Assmann B, Blau N et al (2017) Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis 12(1):1–21

    Google Scholar 

  10. Ali A, Dhahouri N, Almesmari F, Fathalla W, Jasmi F (2021) Characterization of ETFDH and PHGDH mutations in a patient with mild glutaric aciduria type II and serine deficiency. Genes 12(5):703

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Tadmouri G, Nair P, Obeid T, Al Ali M, Al Khaja N, Hamamy H (2009) Consanguinity and reproductive health among Arabs. Reprod Health 6(1):17

    PubMed  PubMed Central  Google Scholar 

  12. Liu X, Wu M, He N, Meng H, Wen L, Wang J et al (2012) NovelPRRT2mutations in paroxysmal dyskinesia patients with variant inheritance and phenotypes. Genes Brain Behav 12(2):234–240

    PubMed  Google Scholar 

  13. Heron S, Grinton B, Kivity S, Afawi Z, Zuberi S, Hughes J et al (2012) PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with Choreoathetosis syndrome. Am J Hum Genet 90(1):152–160

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Gardiner A, Bhatia K, Stamelou M, Dale R, Kurian M, Schneider S et al (2012) PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine. Neurology 79(21):2115–2121

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Schwarz N, Hahn A, Bast T, Müller S, Löffler H, Maljevic S et al (2015) Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia. J Neurol 263(2):334–343

    PubMed  Google Scholar 

  16. Choquet K, La Piana R, Brais B (2015) A novel frameshift mutation in FGF14 causes an autosomal dominant episodic ataxia. Neurogenetics 16(3):233–236

    CAS  PubMed  Google Scholar 

  17. Ebrahimi-Fakhari D, Saffari A, Westenberger A, Klein C (2015) The evolving spectrum ofPRRT2-associated paroxysmal diseases. Brain 138(12):3476–3495

    PubMed  Google Scholar 

  18. Weber A, Kreth J, Müller U (2016) Intronic PRRT2 mutation generates novel splice acceptor site and causes paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) in a three generation family. BMC Med Genet 17(1):1–3

    Google Scholar 

  19. Delcourt M, Riant F, Mancini J, Milh M, Navarro V, Roze E et al (2015) Severe phenotypic spectrum of biallelic mutations inPRRT2gene. J Neurol Neurosurg Psychiatry 86(7):782–785

    PubMed  Google Scholar 

  20. De Giorgis V, Veggiotti P (2013) GLUT1 deficiency syndrome 2013: current state of the art. Seizure 22(10):803–811

    PubMed  Google Scholar 

  21. Klepper J, Scheffer H, Elsaid M, Kamsteeg E, Leferink M, Ben-Omran T (2009) Autosomal recessive inheritance of GLUT1 deficiency syndrome. Neuropediatrics 40(05):207–210

    CAS  PubMed  Google Scholar 

  22. Rotstein M, Engelstad K, Yang H, Wang D, Levy B, Chung W et al (2010) Glut1 deficiency: Inheritance pattern determined by haploinsufficiency. Ann Neurol 68(6):955–958

    PubMed  PubMed Central  Google Scholar 

  23. Vannucci S, Maher F, Simpson I (1997) Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia 21(1):2–21

    CAS  PubMed  Google Scholar 

  24. Brockmann K (2009) The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev 31(7):545–552

    PubMed  Google Scholar 

  25. Pearson T, Pons R, Engelstad K, Kane S, Goldberg M, De Vivo D (2017) Paroxysmal eye–head movements in Glut1 deficiency syndrome. Neurology 88(17):1666–1673

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Hao J, Kelly D, Su J, Pascual J (2017) Clinical aspects of glucose transporter type 1 deficiency. JAMA Neurol 74(6):727

    PubMed  PubMed Central  Google Scholar 

  27. Ng J, Papandreou A, Heales S, Kurian M (2015) Monoamine neurotransmitter disorders—clinical advances and future perspectives. Nat Rev Neurol 11(10):567–584

    CAS  PubMed  Google Scholar 

  28. Surtees R, Rodeck C, Clayton P (1992) Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology 42(10):1980–1980

    PubMed  Google Scholar 

  29. Brun L, Ngu L, Keng W, Ch’ng G, Choy Y, Hwu W et al (2010) Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology 75(1):64–71

    CAS  PubMed  Google Scholar 

  30. Leuzzi V, Mastrangelo M, Polizzi A, Artiola C, van Kuilenburg A, Carducci C et al (2014) Report of two never treated adult sisters with aromatic l-amino acid decarboxylase deficiency: a portrait of the natural history of the disease or an expanding phenotype? JIMD Rep 15:39–45

    PubMed  PubMed Central  Google Scholar 

  31. Wen Y, Wang J, Zhang Q, Chen Y, Bao X (2020) The genetic and clinical characteristics of aromatic L-amino acid decarboxylase deficiency in mainland China. J Hum Genet 65(9):759–769

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lee N, Chien Y, Hwu W (2019) A review of aromatic l-amino acid decarboxylase (AADC) deficiency in Taiwan. Am J Med Genet C Semin Med Genet 181(2):226–229

    CAS  PubMed  Google Scholar 

  33. Montioli R, Dindo M, Giorgetti A, Piccoli S, Cellini B, Voltattorni C (2014) A comprehensive picture of the mutations associated with aromatic amino acid decarboxylase deficiency: from molecular mechanisms to therapy implications. Hum Mol Genet 23(20):5429–5440

    CAS  PubMed  Google Scholar 

  34. Chien Y, Lee N, Tseng S, Tai C, Muramatsu S, Byrne B et al (2017) Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet Child Adolesc Health 1(4):265–273

    PubMed  Google Scholar 

  35. Kojima K, Nakajima T, Taga N, Miyauchi A, Kato M, Matsumoto A et al (2019) Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency. Brain 142(2):322–333

    PubMed  PubMed Central  Google Scholar 

  36. Xu X (2014) MICU1mutation: a genetic cause for a type of neuromuscular disease in children. Clin Genet 87(4):327–328

    PubMed  Google Scholar 

  37. Logan C, Szabadkai G, Sharpe J, Parry D, Torelli S, Childs A et al (2013) Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nat Genet 46(2):188–193

    PubMed  Google Scholar 

  38. Mojbafan M, Nojehdeh S, Rahiminejad F, Nilipour Y, Tonekaboni S, Zeinali S (2020) Reporting a rare form of myopathy, myopathy with extrapyramidal signs, in an Iranian family using next generation sequencing: a case report. BMC Med Genet 21(1):77

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Lewis-Smith D, Kamer K, Griffin H, Childs A, Pysden K, Titov D et al (2016) Homozygous deletion inMICU1presenting with fatigue and lethargy in childhood. Neurol Genet 2(2):e59

    PubMed  PubMed Central  Google Scholar 

  40. Bhosale G, Sharpe J, Koh A, Kouli A, Szabadkai G, Duchen M (2017) Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics. Biochim Biophys Acta Mol Cell Res 1864(6):1009–1017

    CAS  PubMed  Google Scholar 

  41. Musa S, Eyaid W, Kamer K, Ali R, Al-Mureikhi M, Shahbeck N et al (2018) A Middle eastern founder mutation expands the genotypic and phenotypic spectrum of mitochondrial MICU1 deficiency: a report of 13 patients. JIMD Rep 43:79–83

    PubMed  PubMed Central  Google Scholar 

  42. Olpin S, Clark S, Andresen B, Bischoff C, Olsen R, Gregersen N et al (2005) Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency. J Inherit Metab Dis 28(4):533–544

    CAS  PubMed  Google Scholar 

  43. Naiki M, Ochi N, Kato Y, Purevsuren J, Yamada K, Kimura R et al (2014) Mutations inHADHB, which encodes the β-subunit of mitochondrial trifunctional protein, cause infantile onset hypoparathyroidism and peripheral polyneuropathy. Am J Med Genet A 164(5):1180–1187

    CAS  Google Scholar 

  44. Fraser H, Geppert J, Johnson R, Johnson S, Connock M, Clarke A et al (2019) Evaluation of earlier versus later dietary management in long-chain 3-hydroxyacyl-CoA dehydrogenase or mitochondrial trifunctional protein deficiency: a systematic review. Orphanet J Rare Dis 14(1):258

    PubMed  PubMed Central  Google Scholar 

  45. Park HD, Kim SR, Ki CS, Lee SY, Chang YS, Jin DK et al (2009) Two novel HADHB gene mutations in a Korean patient with mitochondrial trifunctional protein deficiency. Ann Clin Lab Sci 39(4):399–404

    CAS  PubMed  Google Scholar 

  46. Ibdah J, Tein I, Dionisi-Vici C, Bennett M, Ijlst L, Gibson B et al (1998) Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation. J Clin Investig. 102(6):1193–1199

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Wanders R, Vreken P, den Boer M, Wijburg F, Van Gennip A, Ijlst L (1999) Disorders of mitochondrial fatty acyl-CoA β-oxidation. J Inherit Metab Dis 22(4):442–487

    CAS  PubMed  Google Scholar 

  48. Choi J, Yoon H, Kim G, Park S, Shin Y, Yoo H (2007) Identification of novel mutations of the HADHA and HADHB genes in patients with mitochondrial trifunctional protein deficiency. Int J Mol Med 20:22–27

    Google Scholar 

  49. Spiekerkoetter U, Sun B, Khuchua Z, Bennett M, Strauss A (2003) Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to ?-subunit mutations. Hum Mutat 21(6):598–607

    CAS  PubMed  Google Scholar 

  50. Olpin S (2013) Pathophysiology of fatty acid oxidation disorders and resultant phenotypic variability. J Inherit Metab Dis 36(4):645–658

    CAS  PubMed  PubMed Central  Google Scholar 

  51. van der Crabben S, Verhoeven-Duif N, Brilstra E, Van Maldergem L, Coskun T, Rubio-Gozalbo E et al (2013) An update on serine deficiency disorders. J Inherit Metab Dis 36(4):613–619

    CAS  PubMed  Google Scholar 

  52. Abdelfattah F, Kariminejad A, Kahlert A, Morrison P, Gumus E, Mathews K et al (2020) Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders. Hum Mutat 41(9):1615–1628

    CAS  PubMed  Google Scholar 

  53. Tabatabaie L, Klomp L, Rubio-Gozalbo M, Spaapen L, Haagen A, Dorland L et al (2010) Expanding the clinical spectrum of 3-phosphoglycerate dehydrogenase deficiency. J Inherit Metab Dis 34(1):181–184

    PubMed  PubMed Central  Google Scholar 

  54. Tabatabaie L, de Koning T, Geboers A, van den Berg I, Berger R, Klomp L (2009) Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics. Hum Mutat 30(5):749–756

    CAS  PubMed  Google Scholar 

  55. Glinton K, Benke P, Lines M, Geraghty M, Chakraborty P, Al-Dirbashi O et al (2018) Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling. Mol Genet Metab 123(3):309–316

    CAS  PubMed  Google Scholar 

  56. Byers H, Bennett R, Malouf E, Weiss M, Feng J, Scott C et al (2015) Novel report of phosphoserine phosphatase deficiency in an adult with myeloneuropathy and limb contractures. JIMD Rep 30:103–108

    PubMed  PubMed Central  Google Scholar 

  57. Angle B, Burton B (2008) Risk of sudden death and acute life-threatening events in patients with glutaric acidemia type II. Mol Genet Metab 93(1):36–39

    CAS  PubMed  Google Scholar 

  58. Schiff M, Froissart R, Olsen R, Acquaviva C, Vianey-Saban C (2006) Electron transfer flavoprotein deficiency: functional and molecular aspects. Mol Genet Metab 88(2):153–158

    CAS  PubMed  Google Scholar 

  59. Lehnert W, Wendel U, Lindenmaier S, Böhm N (1982) Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two brothers. Eur J Pediatr 139(1):56–59

    CAS  PubMed  Google Scholar 

  60. Sweetman L, Nyhan W, Trauner D, Merritt T, Singh M (1980) Glutaric aciduria type II. J Pediatr 96(6):1020–1026

    CAS  PubMed  Google Scholar 

  61. Yamada K, Kobayashi H, Bo R, Takahashi T, Purevsuren J, Hasegawa Y et al (2016) Clinical, biochemical and molecular investigation of adult-onset glutaric acidemia type II: characteristics in comparison with pediatric cases. Brain Dev 38(3):293–301

    PubMed  Google Scholar 

Download references


The authors extend their appreciation to the patients and their caregivers for their participation in this study. We appreciate the help of Dr. Mubashira Hashmi, adult neurologist at the American Center for Neurology and Psychiatry, Abu Dhabi, by sharing her clinical experience in the assessment for our adolescent patient. We would also like to show our gratitude to the metabolic team at Tawam hospital for facilitating the completion of the genetic work up for some of our patients. This research received no specific grant from any funding agency in the public, private, commercial or not-for-profit sectors.


This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Author information




Dr. DAS is an assistant professor of Pediatrics at Faculty of Medicine, Ain Shams University; she is the principal investigator (PI) of the study and the corresponding author. She was responsible for designing the study, case selection, data collection, wrote the manuscript and analysed the data. Dr. AAA is an assistant professor of Department of Histology and Cell Biology, Faculty of Medicine, Ain shams University. Dr. AAA analysed and wrote the molecular data. All authors read, revised and approved the final manuscript.

Corresponding author

Correspondence to Dina Amin Saleh.

Ethics declarations

Ethics approval and consent to participate

The ethical approval for this study was granted by the Institutional Review Board at the American Center for Psychiatry and Neurology in Abu Dhabi, UAE. An informed consent was obtained from all individual participants included in this study.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Saleh, D.A., Attia, A.A.E.M. Shedding light on the phenotypic–genotypic correlation of rare treatable and potentially treatable pediatric movement disorders. Egypt J Med Hum Genet 23, 75 (2022).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:


  • Ataxia
  • Dyskinesia
  • Dystonia
  • Genotype
  • Movement disorders
  • Phenotype
  • Whole-exome sequencing