3-methylglutaconic aciduria

3-methylglutaconic Aciduria with Cataracts, Neurologic Involvement and Neurtropenia

Clinical Characteristics
Ocular Features: 

Descriptions of ocular findings have been limited.  Congenital nuclear cataracts have been described in one patient but lens opacities have been noted in others.

Systemic Features: 

There is considerable heterogeneity in the phenotype with some patients having minimal signs and living to adulthood whereas others succumb to their disease in the first year of life.  The onset of progressive encephalopathy usually occurs in infancy as evidenced by various movement abnormalities and psychomotor delays.  Neonatal hypotonia sometimes progresses to spasticity.  However, other infants are neurologically normal.  Delayed psychomotor development, ataxia, seizures, and dystonia may be seen.  Brain imaging may reveal cerebellar and cerebral atrophy along with brain stem abnormalities.  Neuronal loss, diffuse gliosis, and microvacuolization have been seen on neuropathologic examination.  Dysphagia is common.  Severe neutropenia and recurrent infections may begin in infancy as well.

Increased amounts of 3-methylglutaconic acid are found in the urine while the bone marrow may contain evidence of arrested granulopoiesis. 

Genetics

This autosomal recessive disorder results from homozygous or compound heterozygous mutations in the CLPB gene (11q13.4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported for this condition.

References
Article Title: 

CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder

Wortmann SB, Zietkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, Strom TM, Meitinger T, Rubio-Gozalbo ME, Chrusciel E, Distelmaier F, Golzio C, Jansen JH, van Karnebeek C, Lillquist Y, Lucke T, Ounap K, Zordania R, Yaplito-Lee J, van Bokhoven H, Spelbrink JN, Vaz FM, Pras-Raves M, Ploski R, Pronicka E, Klein C, Willemsen MA, de Brouwer AP, Prokisch H, Katsanis N, Wevers RA. CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder. Am J Hum Genet. 2015 Feb 5;96(2):245-57.

PubMed ID: 
25597510

Behr Early Onset Optic Atrophy Syndromes

Clinical Characteristics
Ocular Features: 

Optic atrophy is the earliest sign in Behr syndrome and may be evident in early childhood.  Nystagmus is a variable feature.  Acuity in the first decade is in the 20/70 to 20/100 range with little worsening in patients followed for a decade or more even though the disc pallor may increase with loss of papillary vasculature.  ERGs are normal but VEPs are usually abnormal.

Systemic Features: 

The nosology of infantile optic atrophy is unclear.   There is no doubt that some familial cases with likely autosomal recessive inheritance lacked (or were not tested for) urinary metabolites considered diagnostic for an optic atrophy disorder with 3-methylglutaconate aciduria (258501) and labeled methylglutaconic aciduria type III (and sometimes Costeff optic atrophy syndrome).  Excretion of 3-methylglutaric acid may also be increased.  But it is also possible that another form of infantile optic atrophy without aminoaciduria also exists.  Early onset (early childhood) optic atrophy, with later (second decade) spasticity, ataxia, extrapyramidal signs and cognitive defects to some degree are common to both.  Dementia, posterior column signs and peripheral neuropathy are more variable clinical signs.  Nerve biopsies and postmortem studies show widespread disease with evidence of chronic neuropathy, neuronal loss, and gliosis.  In Behr's report, the neurologic symptoms remained static after a period of progression.   Others have reported progression with the majority of patients severely handicapped by the third decade of life.

Genetics

Sibs born to consanguineous parents suggest autosomal recessive inheritance in both Behr syndrome with ataxia and in 3-methylglutaconic aciduria, type III.  The latter is most commonly found among Iraqi Jews and is the result of a mutation in the OPA3 gene (19q13.2-q13.3).  The genetic basis for simple Behr infantile optic atrophy is unclear and it is likely that multiple unique entities exist.  This disorder is allelic to an autosomal dominant disorder called Optic Atrophy 3 and Cataracts (165300) but the uniqueness of the latter entity is uncertain.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None known

References
Article Title: 
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