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Correspondence to Amadeo R. Rodriguez, MD, Hamilton Regional Eye Institute, Division of Ophthalmology, Department of Surgery, McMaster University, 2757 King St E., Hamilton, Ont. L8G 5E4.
A 51-year-old woman was seen in the neuro-ophthalmology clinic. She reported difficulties with night vision dating back to approximately age 10 and an abnormal gait since childhood, which was described as unsteady and hesitant with stiffness of both legs. Ten years previously she was noted to have nystagmus by her family practitioner and was referred to an ophthalmologist, who diagnosed her with probable retinitis pigmentosa (RP). At that time, visual evoked potentials showed delayed P100 responses bilaterally. A genetic panel of 59 known RP mutations was tested but did not yield any positive results. Good central visual acuity had been maintained until shortly after her diagnosis of RP, at which point she described a gradual deterioration as well as progressive constriction of her peripheral visual fields.
Her medical history was also notable for never experiencing menarche. She was born to nonconsanguinous parents with no history of vision loss, ataxia, or any known genetic disease. A magnetic resonance imaging scan of the brain had been performed after the onset of her visual decline and 6 years before her neuro-ophthalmic consultation and showed only a few scattered T2/FLAIR white matter hyperintensities.
On examination, visual acuity was hand motion and 20/400. Both pupils were sluggish, with no relative afferent pupillary defect. There were full extraocular movements with a small-amplitude right-beating horizontal nystagmus as well as gaze-evoked nystagmus. Slit-lamp examination revealed a normal anterior segment including a clear crystalline lens. The fundus showed extensive chorioretinal atrophy (Fig. 1). Optical coherence tomography of the macula showed marked thinning of the retina, retinal pigmented epithelium, and choriocapillaris with disorganization and cystic changes in the retinal layers, and there was diffuse constriction of visual fields bilaterally (Fig. 2). Electroretinogram showed reduced a- and b-wave amplitudes in the scotopic maximum and photopic cone responses as well as 30-Hz flicker.
Fig. 1Colour fundus photographs (top) and fundus autofluorescence (bottom). There is severe, widespread retinal atrophy revealing the underlying choroidal vasculature. A few small islands of relatively preserved retinal tissue remain, which have the hyperautofluorescent appearance of devitalized retinal pigmented epithelium (RPE).
Fig. 224-2 Humphrey visual field testing shows marked constriction of the peripheral fields. Optical coherence tomography (OCT) of the macula showing retinal and retinal pigmented epithelium (RPE) atrophy, leading to increased light transmission and a hyper-reflective-appearing choroid.
Examination findings of the remaining cranial nerves were normal. Gait was spastic and slightly wide based. She had bilateral increased lower extremity tone with 5/5 power in all muscle groups. Patellar deep tendon reflexes were increased bilaterally, and there was a flexor plantar response. Sensory examination was normal. There was dysmetria on both finger-to-nose and heel-shin testing.
The patient was referred for a second genetic evaluation, and whole exome sequencing was performed (GeneDx, Gaithersburg, MD). DNA variants were found at c.644T>A;p.V215D and c,3404G>A; p.R1135Q. Analysis of the parents confirmed the variants to be in trans and both were not found in large population cohorts. The V215D variant is a nonconservative substitution, and the R1135Q is a semiconservative amino acid substitution; both were predicted to be deleterious/pathogenic with in silico prediction programs (SIFT, Polyphen2). These findings, the absence of other findings with whole exome sequencing, and the clinical picture supported a diagnosis of Boucher-Neuhauser syndrome.
Boucher-Neuhauser syndrome consists of a constellation of cerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism and is inherited in an autosomal recessive manner. The causative gene, PNPLA6,
is also known as neuropathy target esterase and encodes a lysophospholipase protein localized to the endoplasmic reticulum in photoreceptors and other neurons. It has also been implicated in Leber congenital amaurosis and Oliver McFarlane syndrome, both characterized by early and severe photoreceptor degeneration.
Fundus findings are most often described as choroideremia-like, with pronounced retinal pigmented epithelium and choriocapillaris atrophy and early involvement of the posterior pole.
Boucher-Neuhäuser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature.
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.
Boucher-Neuhäuser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature.
Nystagmus and abnormal smooth pursuit were also common. As in our case, a subset of patients exhibited cortico-spinal tract signs.
The diagnosis of Boucher-Neuhauser syndrome is potentially challenging as there is considerable variability in clinical presentation. Fundus abnormalities may be subtle with relatively preserved central acuity,
In the more frequent cases where vision is significantly compromised, decreased central acuity is accompanied by abnormal colour vision and ring scotomas on visual field testing. Electroretinogram typically shows decreases in both photopic and scotopic responses.
Anterior segment examination is characteristically unremarkable.
In this case, early nyctalopia and peripheral field loss was suggestive of RP; however, the fundus did not show peripheral pigment clumping/bone spicule pigmentation, waxy disc pallor, or marked retinal vessel attenuation, and posterior subcapsular cataract, also commonly seen in RP, was not present. The associated findings of cerebellar ataxia, spasticity, and delayed puberty pointed to the correct diagnosis.
Footnotes and Disclosure
The authors have no proprietary or commercial interest in any materials discussed in this article.
Boucher-Neuhäuser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature.
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