Spectrum of clinical manifestation of methylmalonic acidemia and homocystinuria in a family of six siblings: novel combination of transcobalamin receptor defect (CD320) and cblC deficiency (MMACHC)

Waheed, Nadia; Fayyaz, Zafar; Imran, Ahmad

doi:10.1186/s43042-021-00197-2

Egyptian Journal of Medical Human Genetics

Table 1 Clinical manifestation, laboratory parameters and genetic analysis of all siblings

From: Spectrum of clinical manifestation of methylmalonic acidemia and homocystinuria in a family of six siblings: novel combination of transcobalamin receptor defect (CD320) and cblC deficiency (MMACHC)

	Sibling 1	Sibling 2	Sibling 3	Sibling 4	Sibling 5	Sibling 6
Mutation	MMACHC, c.394C>T Homozygous	MMACHC, c.394C>T Heterozygous	MMACHC, c.394C>T Homozygous	MMACHC, c.394C>T Heterozygous	MMACHC, c.394C>T Homozygous	MMACHC, c.394C>T Homozygous
	CD320, c.262_264del Heterozygous	CD320, c.262_264del Heterozygous		CD320, c.262_264del Heterozygous	CD320, c.262_264del Heterozygous	CD320, c.262_264del Heterozygous
Gender	Female	Female	Female	Male	Male	Male
Current age	11 years	8 years	7 years	5 years	3.5 years	3.5 years
Age at onset	6 years	3 months	6.5 years	3.5 years	3.5 years	3.5 years
1st symptoms	Behavior changes	Developmental milestones not achieved	Psychiatric changes	Learning dis ability	Loss of motor and language skills	Normal
Condition at presentation	No speech, no socialization Lost ambulation Poor appetite Bed ridden	Global developmental delay Only hearing and vision were preserved	Phobias Bouts of cries and laughter	Below average at studies, take too long to learn simple task	Bed ridden Lost ambulation Socialization Speech	Normal
Examination at presentation	Conscious Tone increased Reflexes brisk Plantars upgoing	Conscious Can fix gaze and localize sound Tone increased, reflexes brisk, plantars b/l up going	Conscious Power tone and reflexes were normal	Conscious Power tone and reflexes were normal	Conscious Normal power, tone and reflexes	Conscious Normal power tone and reflexes
Failure to thrive (z score)	Wt; 46 Ht;160 − 1 SD	16 kg 113 cms − 1 SD	12 kg 114 cms − 4 SD	16 kg 107 cms − 1 SD	10 kg 91 cms − 2 SD	10 kg 96 cms − 3 SD
OFC	53 cms	45 cms	46 cms	49 cms	46 cms	46 cms
Megaloblastic anemia	Absent	Absent	Absent	Absent	Absent	Absent
Serum B12 level	Normal	Normal	Normal	Normal	Normal	Normal
Serum homocysteine level	165 umol/l	98 umol/l	102 umol/l	65 umol/l	156 umol/l	70 umol/l
Serum methionine level	45 umol/l	29 umol/l	41 umol/l	35 umol/l	51 umol/l	29 umol/l
Urinary GCMS	Raised MMA	Raised MMA	Raised MMA	Raised MMA	Raised MMA	Raised MMA
Quantitative urinary mma (before tx)	7100 nmol/l	6895 nmol/l	7305 nmol/l	7100 nmol/l	6721 nmol/l	7174 nmol/l
Quantitative urinary mma (after tx)	170 nmol/l	158 nmol/l	145 nmol/l	168 nmol/l	225 nmol/l	198 nmol/l
Brain imaging	Fig. 1a	Fig. 1b	Normal	Normal	Fig. 1c	Normal
Clinical condition after 6 months of treatment	She has become social and interactive, fluent speech walks with ataxic gait	She has started sitting with support, responds to commands and recognizes faces	Little improvement in symptoms	Same	Started walking, active, alert and plays with siblings

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