Transcobalamin II deficiency (TCN2D) is an autosomal recessive disorder with onset in early infancy characterized by failure to thrive, megaloblastic anemia, and pancytopenia. Other features include methylmalonic aciduria, recurrent infections, and vomiting and diarrhea. Treatment with cobalamin results in clinical improvement, but the untreated disorder may result in mental retardation and neurologic abnormalities (summary by Haberle et al., 2009). Hall (1981) gave a clinically oriented review of congenital defects of vitamin B12 transport, and Frater-Schroder (1983) gave a genetically oriented review.

Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord.

Dihydrofolate reductase deficiency is an autosomal recessive metabolic disorder characterized by the hematologic findings of megaloblastic anemia and variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy (Banka et al., 2011) to childhood absence epilepsy with learning difficulties to lack of symptoms (Cario et al., 2011). Treatment with folinic acid can ameliorate some of the symptoms.

3-Methylglutaconic aciduria type I (MGCA1) is a rare autosomal recessive disorder of leucine catabolism. The metabolic landmark is urinary excretion of 3-methylglutaconic acid (3-MGA) and its derivatives 3-methylglutaric acid (3-MG) and 3-hydroxyisovaleric acid (3-HIVA). Two main presentations have been described: one with onset in childhood associated with the nonspecific finding of psychomotor retardation, and the other with onset in adulthood of a progressive neurodegenerative disorder characterized by ataxia, spasticity, and sometimes dementia; these patients develop white matter lesions in the brain. However, some asymptomatic pediatric patients have been identified by newborn screening and show no developmental abnormalities when reexamined later in childhood (summary by Wortmann et al., 2010). Genetic Heterogeneity and Classification of Methylglutaconic Aciduria Methylglutaconic aciduria is a clinically and genetically heterogeneous disorder. Type II MGCA (MGCA2), also known as Barth syndrome (BTHS; 302060), is caused by mutation in the tafazzin gene (TAZ; 300394) on chromosome Xq28. It is characterized by mitochondrial cardiomyopathy, short stature, skeletal myopathy, and recurrent infections; cognitive development is normal. Type III MGCA (MGCA3; 258501), caused by mutation in the OPA3 gene (606580) on chromosome 19q13, involves optic atrophy, movement disorder, and spastic paraplegia. In types II and III, the elevations of 3-methylglutaconate and 3-methylglutarate in urine are modest. Type IV MGCA (MGCA4; 250951) represents an unclassified group of patients who have severe psychomotor retardation and cerebellar dysgenesis. Type V MGCA (MGCA5; 610198), caused by mutation in the DNAJC19 gene (608977) on chromosome 3q26, is characterized by early-onset dilated cardiomyopathy with conduction defects, nonprogressive cerebellar ataxia, testicular dysgenesis, and growth failure in addition to 3-methylglutaconic aciduria (Chitayat et al., 1992; Davey et al., 2006). Type VI MGCA (MGCA6; 614739), caused by mutation in the SERAC1 gene (614725) on chromosome 6q25, includes deafness, encephalopathy, and a Leigh-like syndrome. Type VII MGCA (MGCA7B, 616271 and MGCA7A, 619835), caused by mutation in the CLPB gene (616254) on chromosome 11q13, includes cataracts, neurologic involvement, and neutropenia. Type VIII MGCA (MGCA8; 617248) is caused by mutation in the HTRA2 gene (606441) on chromosome 2p13. Type IX MGCA (MGCA9; 617698) is caused by mutation in the TIMM50 gene (607381) on chromosome 19q13. Eriguchi et al. (2006) noted that type I MGCA is very rare, with only 13 patients reported in the literature as of 2003. Wortmann et al. (2013) proposed a pathomechanism-based classification for 'inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature.'

Folate-responsive immunodeficiency-114 (IMD114) is an autosomal recessive immunologic disorder characterized by the onset of oral ulcers and recurrent skin and respiratory infections in early infancy. Affected individuals have lip fissures, skin sores and abscesses, genital dermatitis, chronic diarrhea, and poor overall growth. Laboratory studies show megaloblastic anemia, thrombocytopenia, and lymphopenia with decreased Ig levels. Some individuals have global developmental delay, often with brain imaging abnormalities. Treatment with folic acid supplementation results in significant clinical improvement of the hematologic and immunologic abnormalities, although neurologic abnormalities, if already present, do not respond to treatment. Early intervention and treatment with folic acid supplementation may prevent or delay neurologic deficits in affected infants (Gok et al., 2023; Shiraishi et al., 2023).