Hereditary Sensory and Autonomic Neuropathy Type 1 responds to large doses of L-serine. It is the only member of the HSAN group that has an effective pharmacologic treatment.
There are a number of inherited and metabolic disorders that respond to large doses of vitamins. These mostly present in adolescents and young adults but can occasionally present later in life.
Thus, a group of 4 disorders respond to large doses of riboflavin. These include 1. Multiple acyl CoA dehydrogenase deficiency, caused by a deficiency of one of 3 enzymes- Electron Transfer Flavoprotein A or B, and ETF dehydrogenase, also called ETF ubiquinone oxidoreductase, responsible for fully 97% of MADD cases. 2. Riboflavin Responsive Exercise Intolerance, caused by a deficiency of mitochondrial FAD transporter, 3. Lipid Storage Myopathy due to deficiency of FAD synthase, and 4. Acyl CoA dehydrogenase 9, or ACAD9 deficiency. All four present with muscle pain, exercise intolerance and a rise in plasma acylcarnitine level of all chain lengths. Episodes of stress associated rhabdomyolysis may occur.
There are two other riboflavin associated disorders: Riboflavin transporter deficiency (RTD) presents as a motor neuronopathy with bulbar involvement, mimicking MND, but can also cause optic and auditory neuropathy. CMTX4 is due to mutations in Apoptosis inducing factor mitochondria associated 1 gene and presents with the classic Charcot Marie Tooth phenotype of hereditary sensorimotor neuropathy. areflexia, pes cavus and additionally auditory neuropathy. Both RTD and CMTX4 show a delayed response to riboflavin supplementation.
Similarly, a number of inherited disorders respond to thiamine. Biotin-thiamine responsive encephalopathy (BTRE) presents with Leigh syndrome- encephalopathy with T2 changes on MRI in basal ganglia, as does E1 alpha pyruvate dehydrogenase deficiency. In the latter, serum and CSF pyruvate and lactate are elevated in equal proportions.
Biotinidase deficiency presents with a neuromyelitic optica phenotype, comprising bilateral visual loss in combination with longitudinally extensive myelopathy. The disorder responds to oral biotin, which should be started ASAP.
Vitamin B12 deficiency and folate deficiency are probably the most frequently diagnosed vitamin deficiencies in clinical practice. They tend to present with similar phenotypes- gait difficulties, peripheral neuropathy, posterior column involvement and psychosis or dementia, with or without macrocytic anaemia.
It is not surprising therefore that inherited defects of B12 or folate pathways would present with similar manifestations. This can occur at any level from defects of absorption from the gut to deficiency of enzymes that produce the active forms of these vitamins. Thus, in Immerslund-Grasbeck syndrome, mutations in the small bowel mucosal transporter called Cubam, leads to megaloblastic anaemia and neurologic manifestations. Cubam consists of 2 subunits- Cubilin, which recognises the B12-IF complex, and Amnionless, which endocytoses them. Thus, defects in either of the putative genes CUB or AMN can lead to IGS.
B12 serves as a co-factor for 2 important reactions in the cell. Firstly, within the mitochondrion, as S-adenosyl cobalamin, it serves as a cofactor to convert methyl-malonyl Co-A to succinyl Co-A, catalysed by methyl-malonyl Co-A mutase. Succinyl Co-A then enters the TCA cycle.
In the cytosol, B12, as Methyl cobalamin, is a methyl donor for the conversion of homocysteine to methionine, catalysed by methionine synthase. Methyl cobalamin is regenerated by donation of a methyl group from 5-methyl tetrahydrofolate, which latter itself becomes demethylated to tetrahydrofolate. THF spontaneously converts to 5,10 methylene tetrahydrofolate, which is then reduced by 5,10 methylene THF reductase to the active methyl donor 5-nethyl THF, thus completing the cycle.
Folate is also a cofactor in the latter reaction, but not the former. Thus both B12 and folate deficiency leads to a rise in serum homocysteine, but only B12 deficiency elevates methyl-malonic acid levels.
The B12/folate pathways overlap with the active form- pyridoxal phosphate (PLP)- of another vitamin- Pyridoxine, or Vitamin B6. Thus PLP is a cofactor for the enzyme cystathionine-beta synthase, which converts homocysteine into cystathionine, and eventually into cysteine. Deficiency of this enzyme leads to the hereditary condition homocystinuria, which has some features of Marfan syndrome. In homocystinuria, serum homocysteine levels and methionine levels are both elevated, unlike in deficiencies of the B12-folate pathway, where homocysteine is elevated but methionine levels are low.
Pyridoxal phosphate activity can also be disrupted by inborn defects of two other amino acid pathways- lysine and proline. In the first instance, deficiency of alpha-amino adipic acid delta-semialdehyde dehydrogenase results in conversion of that lysine metabolite to 6-piperideine carboxylate (P6C). In the second case, a condition called Hyperprolinemia Type II results from the deficiency of 5-Pyrroline carboxylate (P5C) dehydrogenase, leading to elevated levels of P5C. P6C and P5C are both inhibitors of pyridoxal phosphate and thus can again lead to hyper-homocysteinemia.
Disorders of Vitamin E metabolism can lead to two ataxic disorders- Abetalipoproteinemia and Ataxia due to Vitamin E deficiency. Both conditions present with sensory neuronopathy. The former also features retinopathy while the latter features a tremor of the head. The former is due to deficiency of Microsomal triglyceride transfer protein (MTTP) while the latter is due to the deficiency of alpha-tocopherol transfer protein (TTPA) caused by involvement of the putative genes. These two disorders should be considered for all cases of chronic cerebellar ataxia or sensory neuronopathy, which latter presents as non-length dependent sensory neuropathy affecting thighs, arms, etc.
