Complex movement disorders in a sporadic Boucher‐Neuhäuser Syndrome: Phenotypic manifestations beyond the triad

Ling, Helen; Unnwongse, Kanjana; Bhidayasiri, Roongroj

doi:10.1002/mds.22831

Cited by 9 publications

(7 citation statements)

References 8 publications

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“…cases from [7,18]) and peripheral polyneuropathy may be present in substantial fractions as well. Pes cavus [2,4,19] was described by several authors and movement disorders such as focal (craniocervical) dystonia and chorea may develop in BNS [20]. Hypersegmented neutrophils are an inconstant finding in BNS, and so far none of the genetically confirmed cases showed these hematological changes.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…Interestingly, dystonia, epilepsy and migraine were also found in this family. Indeed, there are reports of focal dystonia and chorea in BNS [ 2 , 7 ], suggesting that the physiopathology of these diseases can include the extrapyramidal system, and epilepsy was suspected in 2 previous reported patients [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

Gordon Holmes syndrome due to compound heterozygosity of two new PNPLA6 variants – A diagnostic challenge

et al. 2019

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BackgroundGordon Holmes syndrome (GHS), characterized by cerebellar ataxia and hypogonadotropic hypogonadism (HH), has been related to recessive mutations in PNPLA6 gene.Aims of the studyDescribe one Portuguese family with GHS due to compound heterozygosity of two new PNPLA6 variants.MethodsReport on the clinical presentation, diagnostic and genetic workup to reach GHS diagnosis.ResultsThe index case presented with slight cognitive impairment and primary amenorrhea, developed at the age of 25 a cerebellar syndrome. Her neurological exam revealed ataxia and mild extrapyramidal syndrome. She was born from non-consanguineous parents and had 8 siblings. Two of her sisters also had history of primary amenorrhea, tremor and ataxia. All 3 were diagnosed with HH and previous FMR1 gene screening on her sisters revealed a 51 CGGs allele. However, 2 normal-sized FMR1 alleles were identified on the proband thus excluding the FXTAS diagnosis in the family. Further PNPLA6 variant screening revealed 2 novel variants in compound heterozygosity [c.2404G > C]; [c.4081C > T], which co-segregated with the disease.ConclusionsThis case shows how incomplete studies can be misleading, increases genetic knowledge of GHS and expands its clinical spectrum. The coexistence of a FMR1 intermediate allele in this family constituted an additional challenge in the etiological investigation.

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“…Published B–N case descriptions suggest that additional features may be present, including subcortical T2 white matter hyperintensities [7, 22], basal ganglia [3], midbrain [3], and cortical atrophy [23, 24], pyramidal tract abnormalities and hyperkinetic movements (Table 1). Cognitive decline was noted in our patient and others [1, 4, 7, 25], and we suspect it may constitute a more prominent feature than previously recognized [1].…”

Section: Discussionmentioning

confidence: 99%

“…Gait ataxia in Boucher–Neuhäuser has been typically reported between the first and third decades of life; later ages of onset are rare [1, 3–5]. Although sporadic cases without apparent consanguinity have been reported, most reports are among siblings (about 80 %) [6, 7], often of consanguineous parents [3, 6]. It is unclear whether there is a reporting bias away from sporadic cases in this autosomal recessive disorder, but this seems plausible.…”

Section: Introductionmentioning

confidence: 99%

Compound heterozygous PNPLA6 mutations cause Boucher–Neuhäuser syndrome with late-onset ataxia

et al. 2014

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PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher–Neuhäuser syndrome. Boucher–Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher–Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher–Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient’s genomic DNA from coding exons 26–29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher–Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.

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Complex movement disorders in a sporadic Boucher‐Neuhäuser Syndrome: Phenotypic manifestations beyond the triad

Cited by 9 publications

References 8 publications

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

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

Gordon Holmes syndrome due to compound heterozygosity of two new PNPLA6 variants – A diagnostic challenge

Compound heterozygous PNPLA6 mutations cause Boucher–Neuhäuser syndrome with late-onset ataxia

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