Organic Acidurias

Biotinidase Deficiency

Biotinidase Deficiency, also known as late-onset multiple carboxylase deficiency, is an autosomal recessive disorder of the BTD (biotinidase) gene.388 Biotinidase recycles biotin, which is a water-soluble vitamin and necessary coenzyme for multiple carboxylase enzymes involved in amino acid, fatty acid, and glucose metabolism. The incidence of this disorder is especially high in Brazil. Biotinidase deficiency can be detected with newborn screening and treated with biotin supplementation.920

Multiple case reports and series describe presentation at a young age, with developmental delay, seizures, sensorineural hearing loss, spastic paraparesis, skin rash, infections, acute intermittent ataxia, lactic acidosis, alopecia, and stridor. The main ophthalmologic finding is optic atrophy. The diagnosis is confirmed by a low serum biotinidase level.388 The critical importance of diagnosing biotinidase deficiency lies in the efficacy of treatment, which simply involves oral biotin supplementation. Symptomatic children often have developmental delay and are at risk of irreversible damage to auditory, visual, or central nervous functions. In one study,920 no child with profound biotinidase deficiency detected by newborn screening had auditory or visual loss, and milestones of speech development and motor skills were reached at an appropriate age, emphasizing the need for newborn screening.

Propionic Acidemia

Propionic acidemia is a rare autosomal recessive disorder that leads to chronic metabolic compensation with paroxysmal ketoacidosis, failure to thrive, and mild developmental delay.389 It is characterized by the accumulation of propionyl-CoA inside the mitochondria, secondary to a deficiency of propio- nyl-CoA carboxylase, a biotin-dependent mitochondrial enzyme involved in the catabolism of long-chain fatty acids and amino acids.746,839,936 Clinical manifestations include episodic acidosis and hyperammonemia, leading to irritability, lethargy, tachypnea, vomiting, shock, and death.282,636 Males with propionic acidemia have moderate-to-severe bilateral optic atrophy.389 Rarely, females can develop it too.932

Cobalamin C Deficiency with Methylmalonic Acidemia

Cobalamin C methylmalonic acidemia with homocystinuria is an autosomal recessive inborn error of metabolism that results in the combined dysfunction of two essential coenzymes, adenosylcobalamin and methylcobalamin.736 It

is characterized by progressive maculopathy, failure to thrive, megaloblastic anemia, and neurologic dysfunction.770 Two distinct phenotypes have been described: early and late onset, with early onset carrying a more severe prognosis.736 The associated retinopathy is both developmental and degenerative. Patients present either at birth or later with metabolic decompensation in response to illness and are found to have high methylmalonic acid in the urine. Cobalamin C methylmalonic acidemia is one of the few causes of infantile maculopathy.874 Affected patients have a dramatic disturbance of the retinal pigment epithelium in the macula (sometimes consisting of large areas of macular hypopigmentation with course clumps of pigment), nystagmus, and epileptiform eye movements. The ERG becomes progressively attenuated.770 Some children develop macular coloboma-like changes. Optic atrophy can sometimes accompany these findings.666 Other forms of methylmalonic acidemia without cobalamin C deficiency can also be associated with optic atrophy.932 Treatment with methionine does not rescue the macula or postreceptoral retinal responses represented by the b wave, but has recently been reported to restore normal rod photoreceptor sensitivity in one patient.874

Spinocerebellar Degenerations

Prior to genetic analysis, Harding categorized the autosomal dominant cerebellar ataxias (ADCA) into four types.352,573 Only ADCAI had optic atrophy, which was seen in about 30% of cases. Other neurologic symptoms included supranuclear ophthalmoplegia, basal ganglia dysfunction, amyotrophy, and dementia113,352,513,653,735 Harding’s classification,352 which separated the hereditary ataxias into early onset (predominantly autosomal recessive) and late onset (autosomal dominant), as been further refined by genetic discoveries over the past two decades, leading to a more definitive genomic classification and the possibility of molecular diagnosis. The current classification of hereditary ataxias supplants earlier pathological descriptions of the olivopontocerebellar degenerations.342 ADCA1 is now known to encompass multiple genetic loci, including pedigrees that are now classified as

SCA1, SCA2, and SCA3, and SCA4.222,361,423,573 Optic atrophy is seen more commonly in SCA1, but has been found in SCA2 and SCA3 as well.113

Patients previously diagnosed as having olivopontocerebellar atrophy are now known to carry mutations for SCA1, SCA2, and SCA3.116 These patients show progressive cerebellar ataxia, tremor, spasticity, and speech impairment, which are detailed in chapter 7.113,116,645 Molecular testing of DNA from whole blood is now available to detect the spinocerebellar degenerations.651