Epilepsy, Progressive Myoclonic, 4, With Or Without Renal Failure
A number sign (#) is used with this entry because progressive myoclonic epilepsy-4 (EPM4), also known as action myoclonus-renal failure syndrome (AMRF), is caused by homozygous or compound heterozygous mutations in the SCARB2 gene (602257) on chromosome 4q21.Description
The action myoclonus-renal failure syndrome is an autosomal recessive progressive myoclonic epilepsy associated with renal failure. Cognitive function is preserved (Badhwar et al., 2004). Some patients do not develop renal failure (Dibbens et al., 2009).
For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800).Clinical Features
Andermann et al. (1981) observed 3 patients in 4 French Canadian sibships who developed tremor of the fingers and hands and proteinuria at 17 to 18 years of age. Severe progressive action myoclonus, dysarthria, ataxia, infrequent generalized seizures, and renal failure requiring dialysis and/or renal transplantation ensued between 19 and 23 years of age. Despite severe neurologic disability due mainly to action myoclonus, intelligence remained normal in patients who had survived as long as 14 years after renal transplantation. Nephrosialidosis, another disorder with combined neurologic and renal abnormalities, was excluded.
Badhwar et al. (2004) reported 15 individuals with AMRF from 9 families originating from 5 different countries, including the U.S., Australia, Canada, Cuba, and Germany. Four of the patients had originally been reported by Andermann et al. (1981). Fine tremor of the fingers and hands was the first neurologic symptom with age at onset between 17 and 19 years. Involvement of the head, trunk, and sometimes the tongue occurred with progression of the disorder. Onset of action myoclonus occurred between 14 to 29 years and was the most debilitating feature of the disease. Asynchronous jerks were also present at rest. Many patients became bedridden or wheelchair-bound in the final stages. Convulsive seizures occurred in 73% of patients, with onset between 20 and 28 years. Other neurologic features included ataxia and dysarthria, and 8 patients had cerebellar atrophy on MRI. Proteinuria occurred in all cases between ages 9 to 30 years, and renal failure occurred in 12 of 15 patients within 8 years. Patients presented with neurologic symptoms (5), renal dysfunction (4), or both simultaneously (6). Nine patients died between ages 25 and 35 years, due to respiratory complications, renal failure, or complications of renal transplant. Badhwar et al. (2004) found that dialysis and renal transplantation were effective treatments for the renal failure but did not improve the neurologic condition. Autosomal recessive inheritance was observed.
Vadlamudi et al. (2006) reported 2 unrelated patients with AMRF. The first patient, an Australian man of English descent, developed end-stage renal failure at age 20 years and was treated with dialysis. He also developed a mild, intermittent upper limb action tremor that was exacerbated by stress. At age 24, he had action tremor, myoclonus in the hands and legs, and reported occasional falls while playing sports. He had a renal transplant at age 24. In his late 20s, he developed problems with balance and writing, action myoclonus, postural tremor, gait ataxia, dysarthria, and seizures. The second patient was a Cypriot-born Australian woman born of first cousin parents. She developed focal segmental glomerulosclerosis at age 22 years and had a renal transplant at age 28. Neurologic symptoms began at age 25, with fine action tremor of the hands and deterioration in walking. She later developed worsening tremor, action myoclonus, gait ataxia, and dysarthria. Cognitive function was preserved in both patients. Vadlamudi et al. (2006) emphasized the difficulty in diagnosing this disorder in the early stages because tremor may be the only presenting feature.
Balreira et al. (2008) reported 2 Portuguese sisters, born of consanguineous parents, with AMRF. The first sister presented at age 15 with myoclonic jerks of the upper arms. Symptoms progressed to involve the lower limbs, resulting in gait instability. Horizontal saccades and proteinuria developed at age 18. By age 20, she was totally dependent, unable to write, eat alone, or walk independently, and manifested dysarthria and dysphagia. She developed nephrotic syndrome with thrombocytopenia; renal biopsy showed tubular alterations with vacuolization in distal and collecting tubules and granular material in cortical tubules. There was also deposition of complement components. She died at age 23. A DNA sample from the first sister was not available for testing. The second sister had a similar phenotype with onset at age 17. Horizontal saccades developed at age 20, and by age 21 she presented nephrotic syndrome and was totally dependent 1 year later. At age 23, she had normocytic normochromic anemia and hypoalbuminemia but no thrombocytopenia. She died at age 26 years. Patient fibroblasts showed 10% residual beta-glucosidase (GBA; 606463) activity and an abnormal glycosylation pattern, consistent with depletion of post-Golgi forms of the enzyme. However, leukocytes showed normal GBA activity.
Neuropathologic examination of 1 of the patients reported by Badhwar et al. (2004) showed extraneuronal accumulation of irregularly shaped, refractile, and autofluorescent pigmented granules in the cerebral cortex, the globus pallidus, and some areas of the cerebellar cortex. Renal pathology of several patients showed focal glomerulosclerosis, some with features of collapsing glomerulopathy.
Dibbens et al. (2009) identified 5 unrelated Italian patients with progressive myoclonic epilepsy due to SCARB2 mutations (see, e.g., 602257.0005-602257.0006) who did not develop renal failure. Age at onset ranged between 14 and 23 years, and the disorder was characterized by action myoclonus, tonic-clonic seizures, and later development of ataxia. Four patients died due to refractory seizures and immobility 10 to 15 years after onset, and none of 4 patients had developed renal failure. The fifth patient showed mild proteinuria at age 32 years, 5.5 years after onset. These 5 patients were ascertained from a larger group of 41 patients with progressive myoclonic epilepsy without dementia who were negative for mutations in the CSTB gene (601145), which is responsible for progressive myoclonic epilepsy-1 (EPM1; 254800). The findings of Dibbens et al. (2009) expanded the phenotype associated with SCARB2 mutations to include patients without renal involvement.
Dibbens et al. (2011) provided follow-up of a patient with progressive myoclonic epilepsy without renal failure originally reported by Costello et al. (2009). He had onset of myoclonic epilepsy at age 16 years and became severely disabled, requiring a wheelchair by age 20. At age 27, he had intractable myoclonus, dysarthria, and dysphagia, but cognition remained intact and there was no evidence of renal failure. Electrophysiologic studies indicated a demyelinating peripheral neuropathy, with reduced sensory and motor action potentials and mildly decreased nerve conduction velocities. Dibbens et al. (2011) identified compound heterozygosity for 2 mutations in the SCARB2 gene (602257.0003 and 602257.0007). The findings reemphasized that SCARB2 mutations can cause EPM without renal failure.Inheritance
Andermann et al. (1981) described AMRF in French Canadian sibships. One family had 2 affected sibs, and another was consanguineous. All patients were from the same ethnic group and geographic area, and family names were shared by the ancestors of all cases, consistent with autosomal recessive inheritance of the disorder.Mapping
Studying only 3 unrelated affected individuals with ARMF and their relatives, Berkovic et al. (2008) used homozygosity mapping with single-nucleotide polymorphism (SNP) chips to localize the disorder to chromosome 4q13-q21.Molecular Genetics
Using microarray expression analysis, Berkovic et al. (2008) identified the SCARB2 gene (602257) as a likely site of mutations causing AMRF within the critical region. Mutations in SCARB2 were found in all 3 families used for mapping and subsequently confirmed in 2 other unrelated AMRF families. The mutations were associated with lack of SCARB2 protein (see 602257.0001-602257.0003).
In a Portuguese girl with progressive myoclonic epilepsy and nephrotic syndrome, Balreira et al. (2008) identified a homozygous mutation in the SCARB2 gene (W178X; 602257.0004). A DNA sample from her affected sister was not available for testing.