Objective: To present a case of PNPLA6-related disorder with an expanded phenotype.

Background: PNPLA6-related are autosomal recessive disorders with heterogeneous
clusters of cerebellar ataxia, upper motor neuron dysfunction, chorioretinal dystrophy,
hypogonadotropic hypogonadism with or without anterior hypopituitarism, peripheral
neuropathy, hair anomalies, short stature, and cognitive impairment. Phenotypic
syndromes are known as Boucher-Neuhauser syndrome, Gordon Holmes syndrome,
Oliver-McFarlane Syndrome, Laurence-Moon Syndrome, and HSP39 [1,2,3].

Method: Case report.

Results: A 45 year old male with motor delays in infancy and early childhood, followed by
spasticity in his second decade presented with intermittent head and left upper limb
tremor. Stature was 157.5 cm. Cranial nerves were abnormal for ophthalmoparesis,
horizontal nystagmus, facial muscle weakness, and dysarthria. He had cerebellar
findings of limb and trunk ataxia, and hyperreflexia. Extrapyramidal findings included
left upper limb dystonia, rest and postural tremor, and mild bradykinesia. Sequence
analysis and deletion/duplication testing revealed compound heterozygous variants in
the patatin-like phospholipase domain containing 6 (PNPLA6) gene. PNPLA6
c.2944_2947dup (p.Arg983Glnfs*38) is a pathogenic variant. PNPLA6 c.3889C>T
(p.Pro1297Ser) was classified as a variant of uncertain significance, but was
reclassified to likely pathogenic variant after being identified in symptomatic individuals
from 3 additional families. The variants’ locations were confirmed to be in trans by
parental testing.  His affected brother shared the pathogenic and likely pathogenic pair,
and his unaffected sister carried only the single copy of the pathogenic variant.
Ioflupane I 123 SPECT imaging showed decreased radiotracer uptake within the
posterior putamen bilaterally.  Tremor responded well to
with 300 mg levodopa per day.

Conclusion: This case describes a new likely pathogenic variant in the PNPLA6 gene and expands the phenotypic description of PNPLA6 related disorders to include extrapyramidal abnormalities and abnormal decreased radiotracer uptake in dopamine transporter imaging

References: [1] Synofzik, M, Hufnagel RB, and Züchner S. PNPLA6-Related Disorders. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. 2014 Oct 9 [updated 2015 Jun 11]. [2] Teive HAG, et al. Different Cerebellar Ataxia Phenotypes Associated with Mutations of the PNPLA6 Gene in Brazilian Patients with Recessive Ataxias. Cerebellum 17(3): 380-385 (2018) [3] Tarnutzer A.A., Gerth-Kahlert C., Timmann D. 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 262, 194–202 (2015)

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