PHARC Syndrome, a Rare Genetic Disorder—Case Report

Abstract

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a rare autosomal neurodegenerative disease resulting from mutations on the α/β-hydrolase domain-containing 12 (ABHD12) serine hydrolase encoding gene.1 For the first time reported in 2009 and <40 cases identified,1-4 PHARC patients are often misdiagnosed because the symptoms mimic those of other conditions, including mitochondrial diseases, Refsum disease (RD), Retinitis Pigmentosa (RP), Usher-syndrome and Charcot–Marie–Tooth disease (CMT). In this report, we provide a description of key PHARC findings on a patient whose diagnosis took decades to accomplish. A 29-year-old female patient presented to our neurology consultation with a progressive 10-year-long tremor on both upper limbs, made worst upon activity. The patient had an history of bilateral severe hearing loss starting at age 16 and severe bilateral vision loss with nyctalopia starting at age 19, having been followed at an ophthalmology consultation upon diagnosis of bilateral cataracts and RP. No history of seizures or behavioral problems were reported. The patient presented mild learning disabilities. Family history was unremarkable except for a second degree paternal cousin with a muscular dystrophy. At neurological examination (Video 1), the patient had: low stature and pes cavus; a mild waddling, broad-based ataxic gait and a positive Romberg sign; bilateral upper limb postural jerky tremor; mild titubation of the trunk; mild proximal tetraparesis; abolition of deep tendon reflexes; loss of pinprick sensation up to shin and wrist; loss of vibratory and impaired postural sensation on both hands and feet; moderate appendicular ataxia and dysmetria; mild bilateral ptosis and congenital convergent strabismus of the left eye (no ophtalmoparesis); no alterations of smooth pursuit or saccadic eye movements. Brain MRI (Fig. 1) revealed global moderate cerebral/cerebellar atrophy. Nerve conduction studies revealed demyelination sensorimotor polyneuropathy on both upper and lower limbs (w/o conduction blocks) and conduction velocities of 17–22 m/s (normal >48 m/s, Table S1). The phenotype presented (ataxia with RP, demyelinating neuropathy and hearing loss) suggested RD, but the levels of phytanic acid were normal. A lumbar puncture was unremarkable (including for lactate and pyruvate levels). Blood panels were all within normal ranges (including vitamin A and E, copper studies, α-fetoprotein and autoimmune profiling). A formal neuropsychologic evaluation revealed reduced intelligence and an executive deficit. Usher Syndrome had been previously ruled out. Due to the presence of a demyelinating neuropathy with electrophysiological features suggesting a genetic etiology (i.e. CMT-like phenotype), genetic studies for PMP22 gene duplication were requested but the duplication was absent. Muscular biopsy and mitochondrial DNA sequencing ruled out mitochondrial diseases. Screening for germline variations on the ABHD12 gene and validation by sanger sequencing revealed a nonsense homozygous variant [NM 015600.4: c.1054C > T, p.(Arg352*] leading to the substitution of the arginine 352 for a stop codon (Fig. S1). This variant leads to the truncation of an essential protein, has been previously identified in a patient from the USA and reported as pathogenic. We herein present the first case of a Portuguese PHARC patient, highlighting how despite the presence of typical symptoms earlier diagnosis was precluded due to its rarity. Mitochondrial diseases are often assumed in the presence of cataracts, RP and hearing loss, but the presence of polyneuropathy with demyelinating features should be a red flag for this diagnosis. In turn, in a case of ataxia with RP and a demyelinating polyneuropathy, RD should be considered. However, the absence of the systemic findings classically observed in RD should raise awareness for alternative diagnoses. In a Norwegian study, the authors have shown that the disease incidence was ~1/36,000, a frequency comparable to or even higher than that observed for Friedreich Ataxia.1 A variable phenotype presentation with partial symptoms overlap leads to such misdiagnosis when awareness for the condition is not present. Compound heterozygosity and dosage effects in PHARC have been described,3, 5 and even though no clear genotype–phenotype relationship has been established the same can be envisioned (e.g. expression of aberrant proteins, dominant-negatives, gain-of-function effects and compensation phenomena), contributing to the wide range of presentations. In our case, the presenting neurologic complain was tremor, which is present in some but not most PHARC cases reported to date. Both the observed triad of symptoms (RP, hearing loss and demyelinating polyneuropathy) and ataxia with short stature have been previously noted in other patients. In the other patient sharing the same variant herein reported, pyramidal signs had been noted, but this were absent in our patient. Furthermore, the presence of ptosis (no reported cases) and cognitive impairment with learning difficulties (one case to date) herein reported extend the phenotypic spectrum.1 Altogether, the differential diagnosis of Refsum-like disease (Fig. S2) should be expanded to promptly encompass PHARC syndrome. Our understanding of the underlying pathophysiological mechanisms in PHARC is expanding and its accurate diagnosis becomes critical in order to drive further research on the therapeutic approaches that start to be envisioned. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. P.A.D.B.: 1A, AB, 1C, 3A, 3B M.M.: 1A, 1B, 3B T.L.: 3B M.M.: 3B J.O.: 3B R.B.: 1A, AB, 1C, 3A, 3B Written and verbal informed consents were obtained from the patient. The authors confirm that the approval of the institutional review board was not required for this work We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors declare that there are no conflicts of interest relevant to this work. The authors declare that there are no funding sources or conflicts of interest relevant to this work. The authors declare that there are no additional disclosures to report. Figure S1 Mutation validation chromatogram by Sanger Sequencing revealing a nonsense homozygotic mutation [c.1054C > T, p.(Arg352*] responsible for the substitution of a Arginine 352 for a stop codon. Figure S2 The combination of Ataxia and RP and demyelinating PNP can fit in a restricted number of diagnosis that does not include mitochondrial diseases. PHARC should be thought when facing a Refsum-like phenotype. ARSACS—Autosomal recessive spastic ataxia of Charlevoix-Saguenay; CMT4—Charcot Marie Tooth type 4; PHARC - Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract; CDG1A—Congenital disorder of glycosilation type 1A; ACPHD—Ataxia combined cerebellar and peripheral with hearing loss and DM; AMACRD—Alpha-methylacyl-CoA racemase; NARP—Neuropathy, ataxia, retinitis pigmentosa; SCA 7—Spinocerebellar ataxia type 7; SCA34—Spinocerebellar ataxia type 34; NLC10—neuronal ceroid lipofuscinosis type 10 Table S1 Supplementary details on nerve conduction studies revealing demyelination sensorimotor polyneuropathy on both upper and lower limbs with no conduction blocks and conduction velocities of 17–22 m/s (normal >48 m/s). 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