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ABCD4
| cblJ deficiency (See Disorders of Intracellular Cobalamin Metabolism.) | Combined methylmalonic acidemia & hyperhomocysteinemia / homocystinuria; can present w/low serum B12 levels | 5 persons reported: 3 presented neonatally w/poor growth, feeding problems, hypotonia, respiratory distress, bone marrow suppression, & congenital heart defect. 2 presented in early childhood w/hyperpigmentation & premature graying, & transient ischemic attack (in 1 of 2 children). |
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ACSF3
| Combined malonic & methylmalonic aciduria (OMIM 614265) | High MA & MMA levels in urine or plasma, w/MMA excretion typically higher than MA excretion (MMA/MA >5).
Because C3 (propionylcarnitine) is not ↑, affected infants are not detected by NBS based on a dried blood spot acylcarnitine analysis. 1 | Broad phenotypic spectrum ranging from completely asymptomatic to adults w/neurologic syndromes (seizures, memory problems, psychiatric disease, ±cognitive decline) to children w/a wide range of manifestations (e.g., coma, ketoacidosis, hypoglycemia, FTT, ↑ transaminases, microcephaly, dystonia, axial hypotonia, &/or DD). No biochemical or clinical response to B12 therapy. A largely benign clinical course was reported in an unselected cohort (children-young adult) ascertained through urine NBS in Quebec. 1 |
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ALDH6A1
| Methylmalonate semialdehyde dehydrogenase deficiency (OMIM 614105) | Extremely variable biochemical phenotypes: may be assoc w/3-hydroxyisobutyric, 3-OH propionic aciduria, 3-aminoisobutyric, & β-alanine, &/or transient methylmalonic acidemia/aciduria 2 | Extremely variable clinical phenotypes incl severe ID, dysmorphic features; assoc w/significant brain myelination defects 2 |
AMN
CUBN
| Imerslund-Grasbeck syndrome (OMIM PS261100) | Low serum B12, combined methylmalonic acidemia & hyperhomocysteinemia / homocystinuria, proteinuria in ~50% of affected persons | Megaloblastic anemia, pallor, FTT, recurrent infections, mild proteinuria. |
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CD320
| Transcobalamin receptor defect (TcblR) (OMIM 613646) | Identified on NBS w/an ↑ C3 & ↑ C3/C2 ratio, ↑ plasma & urine MMA, ± ↑ homocysteine & normal or mildly ↑ serum vitamin B12 levels 3 | Largely asymptomatic. Normal biochemistry w/parenteral hydroxocobalamin or oral B12 supplementation. Bilateral central retinal artery occlusion assoc w/hyperhomocysteinemia reported in 1 person. Most reported persons are homozygous for NM_016579.3:c.262_264del (p.Glu88del). 3, 4 |
HCFC1
THAP11
ZNF143
| cblX & cblX-like deficiency (See Disorders of Intracellular Cobalamin Metabolism.) | Combined methylmalonic acidemia & hyperhomocysteinemia | IUGR, congenital malformations, severe DD w/significant ID, early-onset intractable seizures; microcephaly, brain malformations, & dysmorphic features in some persons |
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LMBRD1
| cblF deficiency (See Disorders of Intracellular Cobalamin Metabolism.) | Combined methylmalonic acidemia & hyperhomocysteinemia / homocystinuria; presents w/low serum B12 levels. | Often presents in infancy w/IUGR, poor postnatal growth, feeding difficulties, & DD; may also have stomatitis ± glossitis & congenital heart malformations |
MMACHC
PRDX1
| cblC deficiency (See Disorders of Intracellular Cobalamin Metabolism.) | ↑ plasma concentrations of homocysteine & methylmalonic acid, w/↓ levels of methionine | Frequently assoc w/DD, ID, progressive pigmentary retinopathy, "bull's eye" maculopathy, seizures; highly variable age of onset |
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MLYCD
| Malonyl-CoA decarboxylase deficiency (OMIM 248360) | Combined methylmalonic & malonic aciduria w/significantly ↑ malonic vs methylmalonic acid levels; ↑ C3DC in acylcarnitine profile; ketotic dicarboxylic aciduria; hypoglycemia 5 | Hypoglycemia, metabolic acidosis, ketosis, cognitive impairment, seizures, microcephaly. Cardiomyopathy (left ventricular non-compaction, dilated or hypertrophic) is the leading cause of morbidity & mortality. 5 |
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SUCLA2
| SUCLA2-related mtDNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria (succinyl-CoA ligase deficiency) | Methylmalonic aciduria ranges from 10 to 200 mmol/mol creatinine & is accompanied by ↑ plasma concentrations of lactate, methylcitrate, 3-hydroxyproprionic & 3-hydroxyisovaleric acid, proprionylcarnitine, & C4-dicarboxylic carnitine (C4DC). 6 | Hypotonia, muscle atrophy (presenting at age ~3-6 mos), hyperkinesia, seizures, severe hearing impairment, & growth failure. Leigh syndrome-like disorder, cortical & basal ganglia atrophy, & dystonia. ~30% of affected persons succumb during childhood. |
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SUCLG1
| SUCLG1-related mtDNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria (succinyl-CoA ligase deficiency) | Methylmalonic aciduria ranges from 10 to 200 mmol/mol creatinine & is accompanied by ↑ plasma concentrations of lactate, methylcitrate, 3-hydroxyproprionic & 3-hydroxyisovaleric acid, proprionylcarnitine, & C4-dicarboxylic carnitine (C4DC) 6 | Hypotonia, muscle atrophy, feeding difficulties, & lactic acidosis. Affected infants commonly manifest DD/cognitive impairment, growth restriction/FTT, hepatopathy, hearing impairment, dystonia, & hypertonia. Life span is shortened (median survival: 20 mos). |
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TCN2
| Transcobalamin II deficiency (OMIM 275350) | Combined methylmalonic acidemia & hyperhomocysteinemia. Mostly normal serum B12, but ↓ unsaturated B12 binding capacity & ↓TCII detected by immunoassay. 7 | Pallor, FTT, diarrhea, pancytopenia (can be misdiagnosed as leukemia), recurrent infections, megaloblastic anemia, immunodeficiency, neurologic abnormalities if delayed or inadequate treatment winjectable B12. 7 |
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ZBTB11
| ZBTB11-related intellectual developmental disorder (OMIM 618383) | Biochemical phenotype similar to ACSF3 deficiency w/high MA & MMA levels in urine or plasma, w/MMA excretion typically higher than MA excretion (MMA/MA >5). Because C3 (propionylcarnitine) is not ↑, affected infants are not detected by NBS based on a dried blood spot acylcarnitine analysis. | DD, ID, FTT, microcephaly, cataracts, brain abnormalities; some persons can have isolated ID & no biochemical phenotype. 8 |
