Author Affiliations: Epilepsy Research Program, South Australia Pathology at the Women's and Children's Hospital, North Adelaide, South Australia (Dr Dibbens and Ms Bayly); Department of Neurology, Epilepsy Service, Massachusetts General Hospital, Boston (Drs Karakis and Cole); Department of Neurology, Cork University Hospital, Wilton, Cork, Ireland (Dr Costello); and the Epilepsy Research Centre and Department of Medicine, University of Melbourne, Victoria, Australia (Dr Berkovic).
To report the detection of mutations in the SCARB2 gene in a previously described patient with progressive myoclonus epilepsy (PME) and demyelinating peripheral neuropathy.
Epilepsy Genetics Research Laboratory and Epilepsy Service in a tertiary care center.
A 27-year old male patient with PME with preserved intellect and peripheral neuropathy.
We have solved a previously reported case of PME, preserved intellect, and demyelinating peripheral neuropathy. The patient is a compound heterozygote for 2 mutations in the SCARB2 gene, which has recently been found to be a cause of PME.
Demyelinating neuropathy is a clinical clue to the presence of SCARB2 mutations in PME.
Molecular genetics has revolutionized the challenging problem of diagnosing specific forms of the progressive myoclonus epilepsies (PME). Broadly, PME can be divided up into syndromes in which dementia is prominent (eg, Lafora disease and the neuronal ceroid lipofuscinoses) vs conditions in which cognition is largely preserved (eg, Unverricht-Lundborg disease and myoclonus epilepsy and ragged red fibers).1,2 A rarer cause in the latter category is the action myoclonus renal failure syndrome (AMRF),3 which has recently been shown to be due to mutations in the lysosomal membrane protein SCARB2.4,5
A case report recently published in the Archives described a patient with PME, preserved intellect, and a nonprogressive generalized demyelinating neuropathy.6 The case was extensively investigated and no cause was found, so a novel syndrome was proposed. A diagnosis of AMRF was considered but the absence of renal impairment precluded the diagnosis clinically and the molecular cause was not known at the time of publication. Subsequently, we described cases of PME without renal impairment due to SCARB2 mutations, with subjects being followed up for as long as 15 years without the development of overt renal disease.7 Cases of PME due to mutations in SCARB2 show recessive inheritance, with patients being either homozygous for the same gene mutation or compound heterozygous for 2 different mutations. Features of the aforementioned case, particularly teenage onset, clinical course, and ancestry from French Canada, where AMRF was first described,8 suggested that he may have SCARB2 mutations and he was therefore restudied.
The 27-year-old man had PME beginning at 16 years if age, as previously described.6 He was severely disabled with action myoclonus, requiring a wheelchair at 20 years of age. Since then, his condition has continued to deteriorate, with worsening intractable myoclonus, dysarthria, and dysphagia, difficulties managing his secretions, and full dependence in his everyday activities. Cognitive function, however, has remained intact. Generalized seizures have steadily increased in frequency despite treatment with multiple antiepileptic and antimyoclonic medications, including high doses of piracetam as well as a trial of the low glycemic index diet. His peripheral neuropathy has remained stable by electrodiagnostic criteria, with reduced compound motor and sensory action potential amplitudes, marked prolongation of f-wave latencies, and slowing of conduction velocities to the 30 to 40–m/s range.
Analysis of the SCARB2 gene by direct sequencing, as previously described7 revealed that the patient is a compound heterozygote with 2 different mutations: a nonsense mutation, Q288X, and a splice site mutation, c11187 + 3insT (Figure). In view of this finding, we reevaluated his renal function. His serum creatinine level has been in the reference range and stable throughout his illness. A 24-hour urine collection contained a total protein level of 0.21 g/24 h (reference range, 0.04-0.23 g/24 h). Because a mouse model lacking Scarb2 (Limp2) has deafness,9,10 we performed an audiogram, which showed a small dip at 3-kHz frequencies in the right ear within normal limits; repeated brainstem auditory evoked responses were normal.
Sequencing traces showing the two heterozygous (het) SCARB2 mutations, denoted m1 and m2. The base position of the mutation is indicated by an arrow. PME indicates progressive myoclonus epilepsy.
This case reemphasizes that SCARB2 mutations can cause PME without renal failure. In the initial descriptions of ARMF, it was known that the disorder could begin with either renal or neurological involvement, often separated by a number of years.3,8 Unfortunately, the neurological disorder is relentlessly progressive, with most patients dying of the complications of uncontrolled myoclonus in their third or fourth decade of life. We have followed up some patients for 15 years, from the onset of PME to death, and renal impairment had not developed.7 This case appears to be a further example of either absent or severely delayed development of renal features, suggesting that there are differential pathophysiological mechanisms for the kidney and brain manifestations. Both heterozygous mutations in this case have been seen previously as homozygous mutations in cases of classic AMRF4 (unpublished data), so the specific SCARB2 mutations do not seem to determine the pattern of organ involvement.
A demyelinating hypertrophic peripheral neuropathy is a striking feature in the mouse with Scarb2 (Limp2) deficiency.9 Clinical peripheral neuropathy is not a feature of human patients with AMRF; however, electrophysiological evidence of neuropathy has occasionally been noted, but not extensively studied.3,11 The data previously published on this case demonstrates the longitudinal stability of electrophysiological abnormalities, consistent with a demyelinating neuropathy.6 Thus electrophysiological evidence of a demyelinating neuropathy can be a clinical clue to the presence of a SCARB2 mutation, whose identification is very important in terms of prognosis and genetic counseling.
SCARB2 encodes a lysosomal membrane protein that is a member of the CD36 family of scavenger receptors.12 The protein is widely expressed in human tissues and is thought to function in endosomal/lysosomal mediated protein degradation and recycling.13,14 Patients presenting with progressive myoclonus epilepsy who also have evidence of a peripheral neuropathy should be investigated for mutations in SCARB2..
Correspondence: Samuel F. Berkovic, MD, FRS, Epilepsy Research Centre, Department of Medicine, University of Melbourne, Heidelberg Repatriation Hospital, Austin Health 300 Waterdale Rd, Level 1, Neurosciences Building, West Heidelberg, Victoria 3081, Australia (firstname.lastname@example.org).
Accepted for Publication: November 5, 2010.
Author Contributions:Study concept and design: Dibbens and Berkovic. Acquisition of data: Dibbens, Karakis, Bayly, Costello, and Cole. Analysis and interpretation of data: Dibbens, Karakis, Bayly, and Berkovic. Drafting of the manuscript: Dibbens and Berkovic. Critical revision of the manuscript for important intellectual content: Dibbens, Karakis, Bayly, Costello, Cole, and Berkovic. Obtained funding: Dibbens. Administrative, technical, and material support: Karakis, Bayly, and Cole. Study supervision: Dibbens and Cole.
Financial Disclosure: None reported.
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