Boucher-Neuhauser Syndrome

A number sign (#) is used with this entry because Boucher-Neuhauser syndrome (BNHS) is caused by homozygous or compound heterozygous mutation in the PNPLA6 gene (603197) on chromosome 19p13.

Description

Boucher-Neuhauser syndrome is an autosomal recessive disorder characterized classically by the triad of spinocerebellar ataxia, hypogonadotropic hypogonadism, and visual impairment due to chorioretinal dystrophy. The age at onset is variable, but most patients develop one or more symptoms in the first decade of life. Chorioretinal dystrophy may not always be present. BNHS is part of a spectrum of neurodegenerative diseases associated with mutations in the PNPLA6 gene that also includes spastic paraplegia-39 (SPG39; 612020) (summary by Synofzik et al., 2014).

See also Gordon Holmes syndrome (GDHS; 212840), caused by mutation in the RNF216 gene (609948), which is also characterized by the combination of cerebellar ataxia and hypogonadotropic hypogonadism.

Clinical Features

Neuhauser and Opitz (1975) described a kindred in which 2 brothers and 2 sisters with second-cousin parents had cerebellar ataxia in association with hypogonadotropic hypogonadism. In 3 sibs the onset of cerebellar ataxia was between 12 and 20 years and in the fourth, in the 30s. Hypogonadotropism was reflected in failure of secondary sexual characteristics, eunuchoidism, absence of libido, and infertility. Limber et al. (1989) provided a follow-up on the family described by Neuhauser and Opitz (1975) and demonstrated that the affected members had a syndrome that included, in addition to spinocerebellar ataxia and hypogonadotropic hypogonadism, chorioretinal dystrophy. Limber et al. (1989) also reported another family in which a brother and sister had cerebellar ataxia, hypogonadotropic hypogonadism, and choroidal dystrophy, and noted that an earlier example of this triad had been reported by Boucher and Gibberd (1969) in 2 affected sisters. Limber et al. (1989) recognized the association of spinocerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy as an autonomous single-gene disorder and called it Boucher-Neuhauser syndrome.

Fok et al. (1989) reported a Chinese male with cerebellar ataxia, hypogonadotropic hypogonadism, and peripapillary degeneration with chorioretinal atrophy.

Baroncini et al. (1991) described affected brothers. A review of reported cases indicated that the neurologic signs usually develop during adolescence or early adulthood (range, early childhood to the fourth decade) and are slowly progressive or nonprogressive, whereas ophthalmologic manifestations have an age of onset that varies from the first to the sixth decade of life and a pronounced variability in progression.

Salvador et al. (1995) reported the ophthalmologic findings in a 39-year-old woman with this disorder. Puberty had been delayed although menarche occurred and secondary sex characteristics developed with hormone injections at 17 years of age. Menstruation ceased when the medication was discontinued 4 years later. At 28 years of age, the patient experienced progressive deterioration of balance, and at age 32 years, scanning speech and intention tremor appeared. MRI showed diffuse atrophy of the cerebellar hemispheres. Progressive loss of vision and photophobia began at the age of 37 years. Ophthalmoscopy showed extensive atrophic changes of the retinal pigment epithelium and choriocapillaris in the posterior pole and midperiphery of both eyes.

Rump et al. (1997) described 2 sibs from a nonconsanguineous family with this disorder and reviewed 17 previously reported cases. Rump et al. (1997) considered the presence of features additional to the triad of chorioretinal dystrophy, hypogonadotropic hypogonadism, and spinal cerebellar ataxia likely to intimate a different diagnosis. They also pointed out that the onset of neurologic symptoms may be delayed until the third decade of life and may be variable in nature, hence making the diagnosis difficult.

Synofzik et al. (2014) reported 4 Brazilian sibs, born of consanguineous parents, with Boucher-Neuhauser syndrome. All presented with visual impairment due to chorioretinal dystrophy within the first 3 years of life. Gait ataxia without spasticity developed around age 6 to 7 years. All patients also had hypogonadotropic hypogonadism, including primary amenorrhea in females. Other features included distal muscle wasting, hyporeflexia, and mild cognitive impairment. Brain MRI showed an atrophic pons and cerebellum, as well as a small pituitary. The patients were between 48 and 56 years of age at the time of the report. Five patients from 3 additional families with BNHS were also identified, and all of these patients were adults at the time of the report. The phenotype was somewhat variable: in an Italian family, 1 sister presented at age 12 with visual impairment due to chorioretinal dystrophy, whereas the other sister presented at age 6 with gait ataxia but never developed chorioretinal dystrophy. Both had mild cognitive impairment, hypogonadotropic hypogonadism, and signs of spasticity. In a Brazilian family, 2 brothers presented at age 6 with gait ataxia, and were later found to have chorioretinal dystrophy and hypogonadotropic hypogonadism. Both had normal cognition. A Venezuelan patient was noted to have delayed puberty and visual impairment at age 14; gait ataxia developed around age 20. He did not have cognitive impairment or spasticity. A French man from a fourth family presented with delayed puberty at age 14 and developed gait ataxia in his thirties. He did not have chorioretinal atrophy and had been clinically diagnosed with Gordon Holmes syndrome (212840).

Topaloglu et al. (2014) reported 6 patients from 3 unrelated families with pubertal failure and ataxia who carried biallelic mutations in the PNPLA6 gene. One of the families, of Dutch descent, had previously been reported by Rump et al. (1997). The other 2 families were Turkish. All patients had primary pubertal failure with variable onset of unsteady gait and dysarthria; all had a normal sense of smell. The Turkish patients had no ophthalmologic features, suggesting that such features are not always observed in patients with PNPLA6 mutations.

Inheritance

Baroncini et al. (1991) suggested autosomal recessive inheritance for this disorder because cases had been reported in sibs in a single generation with unaffected parents and consanguinity was identified in 1 instance; males and females were equally affected.

Molecular Genetics

In 9 patients from 4 unrelated families with Boucher-Neuhauser syndrome, Synofzik et al. (2014) identified homozygous or compound heterozygous mutations in the PNPLA6 gene (see, e.g., 603197.0004-603197.0008). All mutations occurred at highly conserved residues and were predicted to disrupt protein function, but in vitro functional studies of the variants were not performed. The mutations in the first 2 families were found by whole-exome sequencing, whereas mutations in the second 2 families were found by direct sequencing of the PNPLA6 gene in 4 additional families with the disorder. A patient from a fifth family who did not have chorioretinopathy also carried biallelic PNPLA6 mutations.

In 6 patients from 3 unrelated families with BNHS, Topaloglu et al. (2014) identified homozygous or compound heterozygous mutations in the PNPLA6 gene (see, e.g., 603197.0011-603197.0012). One of the families had previously been reported by Rump et al. (1997). The mutation in the first family was found by homozygosity mapping and whole-exome sequencing; subsequent mutations were found by direct sequencing of the PNPLA6 gene in 5 additional families. The mutations failed to rescue the neurodegenerative 'Sws' vacuolization phenotype in Drosophila with loss of Pnpla6. Inhibition of NTE activity in a mouse gonadotrope cell line inhibited GNRH (152760)-stimulated luteinizing hormone (LH) exocytosis, without affecting GNRH receptor (GNRHR; 138850) signaling or LH-beta (LHB; 152780) synthesis. The findings were consistent with the mutations resulting in a loss of function. Some patients did not have chorioretinopathy, a finding more consistent with a clinical diagnosis of Gordon Holmes syndrome; Topaloglu et al. (2014) noted that GDHS and BNHS are phenotypically related.