A new PNPLA6 mutation presenting as Oliver McFarlane syndrome
2018-06-21

•We describe a novel PNPLA6 mutation presenting as Oliver McFarlane syndrome.•Retinal detachment may be a so far unknown symptom.•Neurologists have to be aware of the wide PNPLA6-associated spectrum disorders.•In cerebellar ataxia, screening for ocular, skin, or endocrine signs is worthwhile. An 18 year-old female was referred to the Neurology Department in 2015 for evaluation of an unsteady gait she had for a few months. The neurologic examination confirmed an ataxic gait and found a bilateral intentional tremor of the upper and lower extremities as well as a pes cavus. The deep tendon reflexes were diminished; there were no pyramidal signs and no sensory deficits. The patient showed a multidirectional nystagmus and a slight dysarthria. She had a short stature, her hair was thin and sparse and her eyelashes remarkably long. In the light of these findings we considered a syndrome comprising cerebellar ataxia and polyneuropathy and further investigations were undertaken. A brain MRI performed in 2009 and originally considered as normal was re-examined and marked atrophy of the vermis was noted. This finding was confirmed by a new brain CT as well as a new MRI of the cervical spine which also suggested mild medullar atrophy and excluded a cranio-cervical abnormality. The electromyoneurography indicated an axonal sensorimotor polyneuropathy. The ophthalmological exam revealed severely diminished visual acuity in relation to chorioretinal atrophy and severe myopia. The past medical history was remarkable for multiple anterior pituitary deficits including growth hormone deficit, hypoprolactinaemia, hypogonadotropic hypogonadism and mild hypothyroidism. These endocrine disorders had been detected in 2009 when the patient had surgical repair of a patent ductus arteriosus; they had been treated appropriately since that time. The family history was unremarkable for neurological or endocrine disorders; the parents and two sisters were healthy (Fig. 1). The combination of cerebellar ataxia, polyneuropathy, multiple pituitary deficits and chorioretinal dystrophy oriented our diagnostic hypothesis to a PNPLA6-related disorder. This hypothesis was confirmed by sequencing the PNPLA6 gene. A new homozygous mutation in Exon 30 (HGVS: c.[3620C>A];[3620C>A] p.[Ser1207Tyr];[Ser1207Tyr]) was found. The PNPLA6 gene was analyzed by direct sequencing. All coding exons and flanking intronic sequences were amplified using Dye-terminator chemistry (ABI3730XL). Primer sequences are available on request. This technique entailed complete coverage of the entire coding region and flanking intronic sequences. The reported mutation was the only relevant change to be identified. It classifies as a class 4 - likely pathogenic mutation with a 95% likelihood of being pathogenic [[1]Plon S.E. Eccles D.M. Easton D. Foulkes W.D. Genuardi M. et al.Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.Hum. Mutat. 2008; 29: 1282-1291Crossref PubMed Scopus (659) Google Scholar]. The homozygous state of the mutation was confirmed by analyzing the patient's parents' DNA, both showing the mutation at the heterozygous state. By this analysis, a heterozygous deletion associated with a uniparental disomy was excluded. Two years after the initial presentation, the patient developed a retinal detachment in the left eye requiring urgent surgical repair. The patient presently follows regular physiotherapy. In the absence of evidence-based medical treatment for the neurological symptoms, no specific pharmacotherapy has been proposed. Regular endocrinological, ophthalmological and neurological control exams are provided. Although the chances for getting pregnant are reduced in this patient, genetic counseling had been given, assuring the patient that the chances that the off-spring would inherit the disorder are extremely low. The PNPLA6 gene encodes the neuropathy target esterase (NTE) which is an enzyme that catalyzes the deesterification of the membrane phosphatidylcholine into fatty acids and glycerophosphocholine. The gene is thus important for membrane integrity [[2]Hufnagel R.B. Arno G. Hein N.D. Hersheson J. Prasad M. et al.Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes.J. Med. Genet. 2015; 52: 85-94Crossref PubMed Scopus (74) Google Scholar, [3]* 603197 Patatin-like Phospholipase Domain-containing protein 6; PNPLA6.https://www.omim.org/entry/603197Date accessed: September 10, 2017Google Scholar]. The expression of PNPLA6 has been studied in human embryonic tissues and found to be extremely widespread, as it is expressed within the nervous system, in the retina, the trigeminal ganglion, the pituitary gland, the diencephalon, the cerebellum and the ventricular zones of the developing brain; and beyond, in the epidermis, the lens, the extraocular muscles and the nasal epithelium [[2]Hufnagel R.B. Arno G. Hein N.D. Hersheson J. Prasad M. et al.Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes.J. Med. Genet. 2015; 52: 85-94Crossref PubMed Scopus (74) Google Scholar]. In the adult human, the PNPLA6 expression is present in all tissues. Consequently, PNPLA6 mutations have been associated with a panoply of symptoms, affecting different systems, the most prominent ones being anterior hypopituitarism, chorioretinal dystrophy, cerebellar dysfunction, upper or lower motor neuron disease and hair anomalies, as seen in this patient with very long eyelashes and scalp alopecia [[2]Hufnagel R.B. Arno G. Hein N.D. Hersheson J. Prasad M. et al.Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes.J. Med. Genet. 2015; 52: 85-94Crossref PubMed Scopus (74) Google Scholar, 4Synofzik M. Hufnagel R.B. Züchner S. PNPLA6-related disorders.in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. LJH Bean Stephens K. Amemiya A. GeneReviews. 2014: 1993-2018Google Scholar, 5Synofzik M. Gonzalez M.A. Lourenco C.M. Coutelier M. Haack T.B. et al.PNPLA6 mutations cause Boucher-Neuhäuser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum.Brain. 2014; 137 (Epub 2013): 69-77Crossref PubMed Scopus (151) Google Scholar, 6Teive H. Camargo C. Sato M. Shiokawa N. Boguszewksi C. et al.Different cerebellar Ataxia phenotypes associated with mutations of the PNPLA6 gene in Brazilian patients with recessive ataxias.Cerebellum. 2017; https://doi.org/10.1007/s12311-017-0909-yCrossref Scopus (17) Google Scholar]. The severe myopia seen in our patient may have been the main risk factor for the observed retinal detachment, although the retinal PNPLA6 expression could have contributed as well. To the best of our knowledge, this symptom has not yet been reported in humans with PNPLA6 mutations, although retinal degeneration is typical of the disorder [[7]Kmoch S. Majewski J. Ramamurthy V. Cao S. Fahiminiya S. et al.Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness.Nat. Commun. 2015; 6: 5614https://doi.org/10.1038/ncomms6614Crossref PubMed Scopus (62) Google Scholar]. Moreover, to the best of our knowledge, the presence of the patent ductus arteriosus has also not been described in PNPLA6 disorders. A pure coincidence with manifestation of two rare syndromes in the same patient cannot be excluded. These features may present in different clusters, forming distinct but sometimes overlapping syndromes, reason why a continuum spectrum has been proposed and that the following eponyms describe only slightly different syndromes, all due to PNPLA6 dysfunction: Boucher-Neuhäuser syndrome, Gordon Holmes syndrome, Oliver McFarlane syndrome, Laurence Moon syndrome and Spastic paraplegia type 39 [[4]Synofzik M. Hufnagel R.B. Züchner S. PNPLA6-related disorders.in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. LJH Bean Stephens K. Amemiya A. GeneReviews. 2014: 1993-2018Google Scholar, [8]Tarnutzer A. Gerth-Kahlert C. Timmann D. Chang D. Harmuth F. et al.Boucher–Neuhäuser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature.J. Neurol. 2015; 262: 194-202Crossref PubMed Scopus (28) Google Scholar, [9]Garcia-Cazorla A. Mochel F. Lamari F. Saudubra J.M. The clinical spectrum of inherited diseases involved in the synthesis and remodeling of complex lipids. A tentative overview.J. Inherit. Metab. Dis. 2015; 38: 19-40Crossref PubMed Scopus (34) Google Scholar]. A PNPLA6 mutation presenting with pure and exclusive cerebellar ataxia has also recently been reported [[10]Wiethoff S. Bettencourt C. Paudel R. Madon P. Liu Y.T. et al.Pure cerebellar Ataxia with homozygous mutations in the PNPLA6 gene.Cerebellum. 2017; 16: 262-267Crossref PubMed Scopus (23) Google Scholar]. We found that our patient most appropriately classifies as Oliver McFarlane syndrome, since this syndrome comprises all of the clinical manifestations of our patient. In conclusion, the neurologist should be aware of PNPLA6-related disorders, and when suspecting an autosomal recessive cerebellar syndrome, should be attentive to potential yet undetected accompanying endocrinological and ophthalmological manifestations in need of specific and efficient treatment. These symptoms may also inform the differential diagnosis, with the underlying genetic disease only detectable by broader genetic screening beyond the usually screened autosomal recessive spinocerebellar ataxias [[11]Anheim M. Tranchant C. Koenig M. The autosomal recessive cerebellar ataxias.N. Engl. J. Med. 2012; 366: 636-646Crossref PubMed Scopus (252) Google Scholar].