Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2mutations in isolated AMRF features

Action myoclonus-renal failure syndrome (AMRF, OMIM 254900) is characterized by neurological symptoms such as progressive action myoclonus epilepsy (PME), dysarthria, ataxia, and generalized seizures. In addition, patients develop end-stage renal failure (RF) requiring dialysis and/or renal transplantation [1‐4]. The syndrome is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2 which encode a lysosomal-membrane type 2 protein, a member of the CD 36 scavenger receptor-like protein family [5, 6]. β-glucocerebrosidase (β-GC) trafficking requires SCARB2 protein binding for transfer from the endoplasmatic reticulum to the lysosome [6, 7]. Scarb2^-/- mice have hydronephrosis, deficiency in glomerular filtration and peripheral demyelinating neuropathy but no epileptic sign [8]. They show normal cardiac development, but fail to show a hypertrophic response to increased blood pressure and develop dilated cardiomyopathy [9].

We examined an AMRF family with three affected siblings showing typical features [2]. Epileptic seizures and a loss of sensation in the feet occurred in one sister.

The phenotype of the action myoclonus-renal failure syndrome (AMRF) is variable [2]. Some patients do not show evidence of the classic combination of epilepsy and renal failure. Homozygous and compound heterozygous mutations of SCARB2 have been identified in patients who had only progressive myoclonus epilepsy (PME) but no renal failure (RF) [12]. On the other hand, the spectrum of features may possibly be more extended than currently assumed. Here, we report an AMRF family with a novel 1 bp deletion (c.111delC). Of the three affected homozygotes in this family, two had cardiomyopathy (DCM) and all three had demyelinating polyneuropathy (PNP) already before the onset of renal failure. Our findings suggest that DCM and PNP are facultative features of the AMRF phenotype. The detection of PNP in AMRF syndrome is in keeping with observations on scarb2 ^-/- mice where SCARB2-deficiency was found to be associated with upregulation of lysosomal enzymes. This is concomitant with a downregulation of peripheral myelin proteins, accumulation of abnormal inclusions in the outer cytoplasmic zone of Schwann cells, massive loss of peripheral myelin proteins, onion bulbs and other myelin abnormalities, and secondary axonal degeneration, restricted to the peripheral nervous system [8].

A 27-year-old, heterozygous sibling of patients II:1, II:2, II:3, II:4, II:6 had generalized seizures beginning at the age of 14. She also additionally exhibited a reduction of nerve conduction velocity. However, the heterozygous mutation was associated with a detectable AMRF feature only in this sibling, whereas the other heterozygotes in the family (parents, other sister) were by history asymptomatic. This observation suggested that the potential association cannot be strong. To exclude a synergistic effect of two compound heterozygous mutations in the same lysosomal pathway, we additionally sequenced the 11 beta-glucosidase (GBA) exons. No GBA mutation was found. The phenotypical effect of heterozygous SCARB2 mutations has been discussed before in the case of a patient with myoclonus epilepsy and isolated proteinuria [14]. Moreover, earlier studies on families affected by myoclonus epilepsy of Unverricht and Lundborg (EPM1; CSTB mutations; OMIM 254800) reported mild symptoms in heterozygous carriers of the disease allele [15, 16]. In keeping with the latter observation, features of the EPM1 phenotype were described in cstb^+/- mice [17]. Similarly, screening of scarb2 ^+/- mice for AMRF features may help to elucidate the impact of heterozygous SCARB2 mutations.

Therefore, we examined the possibility that the frequency of SCARB2 mutations may be increased in patients with isolated features of AMRF. To further examine the possible relationship between heterozygous mutations in SCARB2 and isolated AMRF signs such as generalized epilepsy (GE) (n = 75), progressive action myoclonus epilepsy (PME) (n = 28), renal failure (RF) (n = 192), polyneuropathy (PNP) (n = 103), and dilated cardiomyopathy (DCM) (n = 85), respective patient samples were scrutinized for putative mutations. We identified two heterozygous PNP patients carrying the SCARB2 mutation p.Y222XfsX located within the highly conserved β-GC binding domain [7]. Before, this frameshift mutation has been identified as being homozygous in a PME patient [12]. In the 103 PNP patients electrophysiological data on the nerve conduction study is not available. However, histopathological analysis of a nerve biopsy taken from one of the two patients carrying the p.Y222XfsX mutation showed evidence of demyelinating PNP. We have not performed any mutational screening of our DCM patients in sarcomeric proteins. None of the other monosymptomatic patients had a SCARB2 mutation. Thus, our findings are not in line with a recent report of high frequency of homozygous or compound heterozygote SCARB2 mutations in patients with isolated PME (clinically resembling Unverricht-Lundborg disease but being negative for CSTB mutations) [12]. However, the frequency of SCARB2 mutations in PME patients may differ between different populations.

Note added in proof: A recent report on a patient with PME and a demyelinating neuropathy affirmed our finding that polyneuropathy belongs to phenotype spectrum of SCARB2 mutation [18, 19].

We conclude that SCARB2 mutations may possibly contribute to the genesis of isolated AMRF-like features in rare cases, but do not appear to be a major cause of these features in the general population. To assess these findings further populations with PNP would have to be examined to see how frequently heterozygote SCARB2 mutations can explain a PNP.