BACKGROUND: Boucher Neuhäuser Syndrome (BNS) is a rare disease with autosomal recessive inheritance defined by the classical triad; early-onset ataxia, hypogonadism and chorioretinal dystrophy.
METHODS: We present two siblings diagnosed with BNS at midlife, identified with homozygous state of a novel PNPLA6 missense mutation. One healthy sibling and the mother were heterozygous carriers of the mutation. The proband presented with the classical triad and the other sibling presented with visual problems at first. The proband was referred to our department by a private Neurologist, in early adulthood, because of hypogonadism, cerebellar ataxia, axonal neuropathy, and chorioretinal dystrophy for further evaluation. The sibling was referred to our department for evaluation, at childhood, due to visual problems. Later, the patient displayed the triad of ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. The unusual medical history of the two siblings led to further examinations and eventually the diagnosis of the first BNS cases in Cyprus. WES-based ataxia in silico gene panel analysis revealed 15 genetic variants and further filtering analysis revealed the PNPLA6 c.3323G > A variant. Segregation analysis in the family with Sanger sequencing confirmed the PNPLA6 homozygous variant c.3323G > A, p.Arg1108Gln in exon 29.
CONCLUSIONS: This highlights the importance of considering rare inherited causes of visual loss, spinocerebellar ataxia, or/and HH in a neurology clinic and the significant role of genetic sequencing in the diagnostic process.

Four members of a three-generation Czech family with early-onset chorioretinal dystrophy were shown to be heterozygous carriers of the n.37C>T in MIR204. The identification of this previously reported pathogenic variant confirms the existence of a distinct clinical entity caused by a sequence change in MIR204. Chorioretinal dystrophy was variably associated with iris coloboma, congenital glaucoma, and premature cataracts extending the phenotypic range of the condition. In silico analysis of the n.37C>T variant revealed 713 novel targets. Additionally, four family members were shown to be affected by albinism resulting from biallelic pathogenic OCA2 variants. Haplotype analysis excluded relatedness with the original family reported to harbour the n.37C>T variant in MIR204. Identification of a second independent family confirms the existence of a distinct MIR204-associated clinical entity and suggests that the phenotype may also involve congenital glaucoma.

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Bietti crystalline dystrophy (BCD) is a rare, genetically determined chorioretinal dystrophy presenting with intraretinal crystalline deposits and varying degrees of progressive chorioretinal atrophy commencing at the posterior pole. In some cases, there can be concomitant corneal crystals noted first in the superior or inferior limbus. CYP4V2 gene, a member of the cytochrome P450 family is responsible for the disease and more than 100 mutations have been defined thus far. However, a genotype-phenotype correlation has not been established yet. Visual impairment commonly occurs between the second and third decades of life. By the fifth or sixth decade of life, vision loss can become so severe that the patient may potentially become legally blind. Multitudes of multimodal imaging modalities can be utilized to demonstrate the clinical features, course, and complications of the disease. This present review aims to reiterate the clinical features of BCD, update the clinical perspectives with the help of multimodal imaging techniques, and overview its genetic background with future therapeutic approaches.

Boucher-Neuhäuser syndrome (BNHS) is characterized by chorioretinal dystrophy, hypogonadotropic hypogonadism, and cerebellar dysfunction and atrophy. The disorder has been associated with biallelic pathogenic variants in the patatin-like phospholipase domain-containing protein 6 (PNPLA6) gene. We present an individual with a clinical diagnosis consistent with BNHS who lacked any PNPLA6 variants but on quartet family exome sequencing had a de novo variant in the hexokinase 1 (HK1) gene (NM_000188.2 [GRCh37/hg19]: g.71139826G>A, c.1240G>A, p.Gly414Arg), suggesting genetic heterogeneity for BNHS. Longitudinal follow-up indicated neurological deterioration, neuropsychiatric symptoms, and progressive cerebellar atrophy. The BNHS phenotype overlaps and expands the known HK1 genotypic and phenotypic spectrum. Individuals with variants in HK1 should undergo evaluation for hypogonadotropic hypogonadism, potentially amenable to treatment.

To describe the clinical presentation and long-term clinical features of a molecularly confirmed cohort with Cohen syndrome.
Twelve patients with Cohen syndrome aged 0.2-13.9 years from 8 families with a median follow-up of 7 years were enrolled to the study. Genetic analyses were made by VPS13B and whole-exome sequencing analyses.
Biallelic VPS13B variants, including 3 nonsense, 1 frameshift, and 1 splice-site variant, and a multiexon deletion were detected. Prader-Willi syndrome-like features such as hypotonia, small hands, round face with full cheeks, almond-shaped eyes, and micrognathia were observed in all infantile patients. Beginning from age 4 years, it was noticed that the face gradually elongated and became oval. The typical facial features of Cohen syndrome such as a long face, beak-shaped nose, and open-mouth appearance with prominent upper central incisors became evident at age 9. Other Cohen syndrome features including retinopathy (11/11), neutropenia (11/12), truncal obesity (5/12), and myopia (5/11) were detected at the median ages of 7.8, 7, 7.5, and 5 years, respectively. Eleven patients aged older than 5 years at their last examination had severe speech delay.
A differential diagnosis of Cohen syndrome in the infancy should be made with Prader-Willi syndrome, and that the typical facial features for Cohen syndrome is prominent at age 9 years, when retinopathy, neutropenia, and truncal obesity become evident. Moreover, adding the severe speech delay to the diagnostic criteria should be considered.

Background: Boucher-Neuhäuser syndrome (BNS, MIM 215470) is a rare autosomal recessive syndrome caused by mutations in the PNPLA6 gene. Few BNS cases have been reported for functional validation at the RNA level. Herein, we report on the family of a 17-year-old girl with clinical characteristics of BNS, genetic validation, and a systematic review of PNPLA6 variants related to BNS. Methods: Clinical data and blood samples were collected from the patient and their parents, and whole-exome sequencing was performed and confirmed by Sanger sequencing. RNA-sequencing (RNA-Seq) and quantitative RT-PCR (qRT-PCR) were performed, and the three-dimensional protein structures of the variants were predicted. Results: We report a 17-year-old female with progressive night blindness since the age of four, primary amenorrhea, and non-development of secondary sexual characteristics. Her impaired vision was diagnosed as retinal pigmentary degeneration of the retina. She had congenital hypogonadotropic hypogonadism (CHH) but no cerebellar ataxia at present. Two novel compound heterozygous variants (c.2241del/p.Met748TrpfsTer65 and c.2986A>G/p.Thr996Ala) of the PNPLA6 gene (NM_006702.4) were identified by whole-exome sequencing. The former variant was carried from her healthy father and has not been reported previously. The latter was inherited from her healthy mother and was noted in a report without functional studies. The RT-PCR results showed that the mRNA expression of PNPLA6 was lower in this patient and her father than in the control group. She was diagnosed with BNS. Both variants (c.2241del and c.2986A>G) were likely pathogenic according to the ACMG criteria. The novel variants in the PNPLA6 gene related to Boucher-Neuhäuser syndrome were summarized in this article. Conclusion: The possibility of Boucher-Neuhäuser syndrome should be considered when patients present with night blindness, impaired vision, and hypogonadotropic hypogonadism. Gene sequencing is currently the primary diagnostic method. Herein, novel compound heterozygous variants of PNPLA6 were identified in a BNS patient, and its function was verified at the RNA level. The PNPLA6 c.2241del variant is novel and potentially pathogenic, expanding the mutation spectrum in PNPLA6.

A wide spectrum of neurodegenerative diseases has been associated with pathogenic variants in the PNPLA6 (patatin-like phospholipase domain-containing protein 6) gene, including spastic paraplegia type 39, Gordon-Holmes, Boucher-Neuhauser, Oliver-Mc Farlane, and Laurence-Moon syndromes. These syndromes present variable and overlapping clinical symptoms, encompassing cerebellar ataxia, hypogonadotropic hypogonadism, chorioretinal dystrophy, spastic paraplegia, muscle wasting, peripheral neuropathy, and cognitive impairment. In the present study, we performed a wide genetic screening in 292 patients presenting with ataxia or spastic paraplegia using a probe-based customized gene panel, covering >200 genes associated with spinocerebellar diseases. We identified six novel and four recurrent PNPLA6 gene variants in eight patients (2.7%). Six patients presented an infantile or juvenile onset (age <18), and two patients had an adult onset. Cerebellar ataxia was observed in seven patients and spastic paraplegia in one patient. Progression of cerebellar symptoms was slow in all patients, who retained ambulation even after a mean disease duration of 15 years. Brain MRI showed cerebellar atrophy in 6/8 patients, more pronounced in superior and dorsal vermis lobules (I to VII). Additional clinical features included hypogonadotropic hypogonadism (5/8), growth hormone deficiency (2/8), peripheral axonal neuropathy (4/8), cognitive impairment (3/8), chorioretinal dystrophy (2/8), and bilateral vestibular areflexia with a reduced visual vestibule-ocular reflex (1/8). In accordance with previous studies, chorioretinal dystrophy was the most frequent presenting symptom in early onset patients, hypogonadotropic hypogonadism in juvenile onset cases, and cerebellar ataxia in adult patients. One patient had an initial clinical presentation compatible with Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS), but no pathological expansions in the RFC1 gene. In conclusion, patients with PNPLA6 variants present a variable age of onset spanning from infancy to adulthood, and each clinical symptom has an age-dependent manifestation thus requiring a multi-systemic diagnostic approach. The description of patients presenting very late-onset cerebellar ataxia suggests that PNPLA6 genetic screening should also be considered in the diagnostic workout of adult cerebellar ataxia.

Boucher-Neuhäuser Syndrome (BNS) is a rare autosomal recessive disorder characterized by hypogonadotropic hypogonadism, spinocerebellar ataxia, and chorioretinal syndrome, and associated with a variant in the PNPLA6 gene. Although many reports have mentioned the presence of cognitive impairment, a neuropsychological assessment of a BNS case has never been published. Here, we provide a detailed description of a young adult patient with BNS who has a homozygous pathogenic variant in the PNPLA6 gene.
A 21-year-old man with progressive ataxia and a history of hypogonadotropic hypogonadism and chorioretinal dystrophy was diagnosed with BNS. A comprehensive cognitive evaluation was performed, requiring the ad hoc selection and adaption of neuropsychological tests to overcome visual and motor impairments that characterize this syndrome.
The patient presented an intact global cognitive profile with selective executive dysfunction and mild verbal reasoning dysfunction. In particular, attentional-inhibitory control, working memory, and set switching were impaired, and inadequate development of conceptual knowledge and abstract reasoning was observed.
This is the first report of an explicitly documented comprehensive neuropsychological assessment in a patient with BNS. The battery we composed is an example of a methodology that can be used to conduct a detailed cognitive examination without being penalized for physical impairment.Further studies are needed to define the typical cognitive features that characterize BNS and possibly identify its cognitive phenotype(s).

Purpose: The current study aims to raise awareness of Boucher - Neuhauser syndrome (BNHS) that occurs as a rare phenotype due to biallelic pathogenic variants in the PNPLA6 gene.Methods: Detailed family histories and clinical data were recorded. Whole exome sequencing was performed and co-segregation analysis of the family was done by sanger sequencing. Also, review of 28 molecularly confirmed patients with BNHS from the literature was evaluated.Results: We identified a missense homozygous variant (c.3524 C > G (p.Ser1175Cys)) in the PNPLA6 gene, which explains the phenotype of the patient and neurologic, ophthalmologic, endocrine, and genetic evaluations established a diagnosis of BNHS. Symptoms, ethnicity, clinical and genetic findings of 28 molecularly confirmed patients with BNHS from the literature were also presented.Conclusion: We present the main findings of a Turkish family with BNHS together with detailed clinical and genetic profiles of patients diagnosed as BNHS that have been molecularly confirmed in the literature so far.