movement disorders

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

Wilson Disease

Clinical Characteristics
Ocular Features: 

The cornea and lens have visible copper deposition.  This is responsible for the classic (though non-pathognomonic) copper-colored Kayser-Fleischer ring in the cornea where evidence of copper deposition can be visualized in the posterior stroma and in the endothelium.  About 50-60% of patients at any point have evidence of such copper deposition but the number rises to 90% in patients with neurologic and psychiatric symptoms.  Copper deposition in the lens leads to a ‘sunflower’ or 'sunburst' cataract consisting of a greenish central disc in the anterior capsule with spoke-like radial cortical opacities.  Eye involvement in Wilson disease usually does not lead to significant impairment of vision.

Systemic Features: 

This is a disorder of copper metabolism.  It is associated with severe liver disease, often beginning with signs of recurrent jaundice, sometimes a hepatitis-like illness, and often culminating in liver failure.  Hepatobiliary malignancies are a significant risk, occurring in more than 1 percent of patients.  Neurologic toxicity leads to various movement disorders such as tremors, poor coordination, dystonia, and choreoathetosis.  Many patients have mental symptoms such as depression, neurotic behavior, and personality disturbances.  Some have a mask-like facies and pseudobulbar symptoms.  Symptoms can appear anytime from 3 years of age to over 50.  Other organs such as kidney, pancreas, heart and even joints may also be involved.

Patients often have a low serum ceruloplasmin, low copper levels, increased urinary excretion of copper, and increased concentration of copper in the liver.

Genetics

This is an autosomal recessive disorder caused by homozygous or doubly heterozygous mutations in the ATP7B gene (13q14.3).  Heterozygotes usually do not develop symptoms but may have reduced serum ceruloplasmin levels.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Zinc and/or copper chelating agents such as D-penicillamine or trientine have long been used with benefit but the treatment must be used throughout life.  Reduced copper intake may also be helpful.  An orthotopic liver transplant can prolong life in selected patients.

References
Article Title: 

Hepatobiliary malignancies in Wilson disease.

Pfeiffenberger J, Mogler C, Gotthardt DN, Schulze-Bergkamen H, Litwin T, Reuner U, Hefter H, Huster D, Schemmer P, Czlonkowska A, Schirmacher P, Stremmel W, Cassiman D, Weiss KH. Hepatobiliary malignancies in Wilson disease. Liver Int. 2014 Nov 4. [Epub ahead of print].

PubMed ID: 
25369181

A practice guideline on Wilson disease

Roberts EA, Schilsky ML; Division of Gastroenterology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada. A practice guideline on Wilson disease. Hepatology. 2003 Jun;37(6):1475-92. Erratum in: Hepatology. 2003 Aug;38(2):536.

PubMed ID: 
12774027
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