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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
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