Boucher–Neuhäuser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature

Abstract

The combination of progressive cerebellar degeneration, hypogonadotropic hypogonadism and chorioretinal dystrophy defines the rare Boucher-Neuhäuser syndrome (BNS), which has recently been linked to autosomal-recessive mutations in the PNPLA6 gene in four index patients. Here we present two novel unrelated patients with BNS, where we identified four recessive PNPLA6 mutations (3 of them novel) as the genetic cause, using a targeted high-throughput approach. This finding provides the first replication from independent families that BNS is caused by PNPLA6 and, moreover, highlights PNPLA6 as the major gene leading to BNS. Given the fact that the major gene causing BNS has thus now been identified, we summarize the spectrum of clinical presentations and phenotype evolution of BNS based on a systematic in-depth review of the literature of previously published cases (n = 40). Both the two cases presented here and our review of the literature propose that the clinical presentation of BNS can be variable regarding both the age (ranging from 1 to 40 years) and the clinical symptoms at onset (cerebellar ataxia in 38 %; vision loss in 36 %; delayed puberty in 26 %). A substantial fraction of BNS cases may present with relatively selective atrophy of the superior and dorsal parts of the cerebellar vermis along with atrophy of the cerebellar hemispheres on MRI, while brainstem or cortical changes on MRI seem to be present only in small fractions. Also in the literature, no other major genetic causes of BNS other than PNPLA6 mutations were identified.

Pure Cerebellar Ataxia with Homozygous Mutations in the PNPLA6 Gene

“…Recently, reports of biallelic mutations in the PNPLA6 gene originally causative for SPG39 [4] have extended the phenotypic spectrum, frequency and geographic occurrence [14], e.g. compound heterozygous mutations have been reported in a sporadic BNS-patient with late-onset gait ataxia and mild retinal changes [15], the first two non-Caucasian PNPLA6 cases of Japanese origin have been published [16], and PNPLA6 was identified as the genetic cause in several families with Laurence-Moon syndrome (LNMS, MIM #245800), childhood blindness, Oliver-McFarlane syndrome (OMCS, MIM #275400) and Leber congenital amaurosis (LCA1, MIM #204000) [7, 8].…”

Severe chorioretinal atrophy in Boucher-Neuhauser syndrome

“…2 Fundus findings are most often described as choroideremia-like, with pronounced retinal pigmented epithelium and choriocapillaris atrophy and early involvement of the posterior pole. 2,3 A recent review of published cases reported that 36% of patients presented first with a complaint of progressive vision loss and approximately 12% were legally blind. 3 Nystagmus and abnormal smooth pursuit were also common.…”

Targeted Gene Panel Sequencing for Molecular Diagnosis of Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism

“…Genomic DNA was extracted from peripheral blood leukocytes using the Gentra Puregene Blood Kit (Qiagen, Hilden, Germany). A targeted panel was designed using 69 genes that were known to be involved in hypothalamus/pituitary development [15][16][17][18][19][20][21][22][23], GnRH neuronal migration [10,11,[24][25][26][27][28][29][30][31][32][33][34], synthesis and secretion of GnRH [35][36][37][38][39][40][41][42], IGD associated neurological disorders [43][44][45][46][47][48], and rare syndromes [26,30,[49][50][51][52][53][54][55][56][57] associated with hypogonadism ( Table 1S, Supporting Information). For compreh...…”