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Abstracts & Commentary
Sources: Zimprich A, et al. Nat Genet. 2001;29:66-69; Zhou B, et al. Nat Genet. 2001;28:345-349; Rampoldi L, et al. Nat Genet. 2001;28:119-120.
In the last several months, the genetic mutations responsible for 3 rare neurologic conditions have been discovered: myoclonus-dystonia, Hallervorden-Spatz syndrome (HSS), and neuroacanthocytosis. These papers will alter the diagnosis of adult and pediatric patients with unusual movement disorders. More importantly, they will provide important insights into the biologic mechanisms responsible for these unusual conditions.
Myoclonus-dystonia is a rare illness characterized by "lightning-like" myoclonic jerks affecting the proximal limbs and trunk. Symptoms typically begin in the first or second decade of life, and are often accompanied by focal dystonia manifesting as torticollis or writer’s cramp. The disorder is autosomal dominant with incomplete penetrance, although some sporadic cases may occur. Affected patients in the same family may have myoclonus alone, myoclonus plus dystonia, or even dystonia in isolation. A pathognomonic feature of the disorder is the exquisite response of myoclonic jerks to alcohol. Psychiatric pathology is extremely common in affected patients, particularly obsessive-compulsive disorder and panic attacks.
The disease locus for myoclonus-dystonia was mapped to chromosome 7q21 by several groups. Using genomic sequence from the Human Genome Project, Zimprich and colleagues detected loss-of-function mutations in the e-sarcoglycan gene in all index patients with myoclonus-dystonia. Penetrance depends on the parental origin of the disease allele, as most patients inherit the diseased gene from their father. e-sarcoglycan is 1 of 5 members of the sarcoglycan family of proteins that code for the transmembrane component of the dystrophin-glycoprotein complex. Mutations in the other members of this family cause autosomal-recessive limb-girdle muscular dystrophy. e-sarcoglycan is broadly expressed in both non-neural and neural tissues. It is striking that alteration of a protein component of the cell membrane is responsible for myoclonus-dystonia and its associated psychiatric conditions. This suggests the possibility that alteration of neuronal wiring or connections may be responsible for both disorders.
HSS is a disease dreaded by pediatric neurologists. An autosomal recessive disorder, it typically begins within the first 2 decades of life, causing relentless, progressive dystonia, parkinsonism, and pigmentary retinopathy. HSS may begin in adulthood, with clinical presentations that include palilalia, facial tics, severe intermittent dystonia, or parkinsonism. All affected patients accumulate high levels of iron in the globus pallidus, producing the so-called "eye of the tiger" sign on MRI imaging. Zhou and colleagues first mapped the HSS locus to chromosome 20p13, and then identified the responsible gene, pantothenate kinase 2 (PANK2), in patients with classic early onset HSS and adults with HSS as well.
PANK2 is an essential enzyme in coenzyme A biosynthesis, catalyzing cytoplasmic phosphorylation of pantothenate (vitamin B5). The resulting product, phosphopantothenate, normally condenses with cysteine. PANK2 deficiency thus leads to an accumulation of cysteine which auto-oxidizes in the presence of iron, producing free radicals that may accelerate cell death. Nonheme iron is highest in globus pallidus and the pars reticulata of the substantia nigra, areas that are most severely affected in HSS. The discovery of PANK2 suggests a possible therapeutic approach for patients with HSS. Using antioxidants such as vitamin E and CoQ10 and supplemental pantothenate, it may be possible to prevent or slow cell death. The discovery also allows patients to be diagnosed definitively, as genetic testing for patients suspected of having HSS is currently available through the University of Chicago.
The final report from Rampoldi and colleagues details the discovery of the gene for neuroacanthocytosis. This autosomal recessive disorder afflicts patients in late teens and adulthood. Affected patients develop chorea, psychiatric disturbances, epilepsy, oral self-mutilatory behavior, and peripheral neuropathy. Current diagnosis depends on the demonstration of acanthocytes in the peripheral blood smear.
The disorder was mapped to chromosome 9q21 in several Japanese families, and the responsible gene, chorein, was finally isolated. Chorein is expressed throughout the brain and is homologous to proteins that control cycling of transmembrane proteins of the trans-Golgi apparatus. This may explain the development of acanthocytes due to disruption of the plasma membrane structure.
These 3 discoveries demonstrate the power of genetics to expand our understanding of neurologic illness. In the short term, neurologists will be able to definitively diagnose diseases that were previously only recognized and suspected by clinical features alone. In the long term, the development of animal models of these disorders will allow for rationale drug design and new treatments. —Steven Frucht
Dr. Frucht, Assistant Professor of Neurology, Movement Disorders Division, Columbia-Presbyterial Medical Center, is Assistant Editor of Neurology Alert.