PNPLA6 Disorders

Clinical characteristics: PNPLA6 disorders span a phenotypic continuum characterized by variable combinations of cerebellar ataxia; upper motor neuron involvement manifesting as spasticity and/or brisk reflexes; chorioretinal dystrophy associated with variable degrees of reduced visual function; and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics). The hypogonadotropic hypogonadism occurs either in isolation or as part of anterior hypopituitarism (growth hormone, thyroid hormone, or gonadotropin deficiencies). Common but less frequent features are peripheral neuropathy (usually of axonal type manifesting as reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting); hair anomalies (long eyelashes, bushy eyebrows, or scalp alopecia); short stature; and impaired cognitive functioning (learning disabilities in children; deficits in attention, visuospatial abilities, and recall in adults). Some of these features can occur in distinct clusters on the phenotypic continuum: Boucher-Neuhäuser syndrome (cerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism); Gordon Holmes syndrome (cerebellar ataxia, hypogonadotropic hypogonadism, and – to a variable degree – brisk reflexes); Oliver-McFarlane syndrome (trichomegaly, chorioretinal dystrophy, short stature, intellectual disability, and hypopituitarism); Laurence-Moon syndrome; and spastic paraplegia type 39 (SPG39) (upper motor neuron involvement, peripheral neuropathy, and sometimes reduced cognitive functioning and/or cerebellar ataxia).

Diagnosis/testing: The diagnosis of a PNPLA6 disorder is established in a proband with suggestive findings and biallelic PNPLA6 pathogenic variants in trans configuration identified by molecular genetic testing.

Management: Treatment of manifestations: Management is symptomatic and individually tailored.

1. Ataxia. Continuous training of speech and swallowing, fine-motor skills, gait, and balance

2. Spasticity. Interventions to improve strength and agility and to prevent contractures, such as physical therapy, assistive walking devices and/or ankle-foot orthotics, and drugs to reduce muscle spasticity

3. Chorioretinal dystrophy. Low vision aids when central acuity is reduced; involvement with agencies for the visually impaired, mobility training, and skills for independent living

4. Hypothyroidism. Hormone replacement therapy as soon as identified

5. Growth hormone deficiency. Hormone replacement therapy during childhood and/or adolescence as indicated

6. Hypogonadotropic hypogonadism. Hormone replacement therapy at the expected time of puberty

Surveillance: Periodic multidisciplinary reevaluations to assess disease progression and modify treatment strategies.

Agents/circumstances to avoid: Alcohol; obesity; inactive, sedentary lifestyle; exposure to medications or chemicals that exacerbate neuropathy.

Genetic counseling: PNPLA6 disorders are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PNPLA6 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the PNPLA6 pathogenic variants in the family have been identified, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.