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.

• Ataxia. Continuous training of speech and swallowing, fine-motor skills, gait, and balance
• 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
• Chorioretinal dystrophy. Low vision aids when central acuity is reduced; involvement with agencies for the visually impaired, mobility training, and skills for independent living
• Hypothyroidism. Hormone replacement therapy as soon as identified
• Growth hormone deficiency. Hormone replacement therapy during childhood and/or adolescence as indicated
• 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.

Suggestive Findings

A PNPLA6 disorder should be suspected in individuals with a combination of the following clinical features, neuroimaging, and family history (rather than any of these features in isolation).

Clinical features

• Cerebellar ataxia (associated with cerebellar atrophy) starting before age 50 years and
• Upper motor neuron involvement presenting as spasticity and/or brisk reflexes
• Chorioretinal dystrophy starting before age 50 years and leading to variable degrees of reduced visual function, including blindness. The diagnosis of chorioretinal dystrophy may be established by ophthalmologic assessment, including visual acuity, visual field testing, fundoscopy, and optic coherence tomography (OCT) [Synofzik et al 2015]:
  • It is usually characterized by diffuse atrophy of choroidal vessels and retinal pigment epithelium on fundoscopy, leading to complete loss of the choriocapillaris layer and the retinal pigment epithelium [Deik et al 2014, Synofzik et al 2015], including death of photoreceptors and retinal thinning accompanied by lipofuscin deposition [Kmoch et al 2015].
  • OCT can detect thinning of the retina, loss of layered retinal architecture, and effacement of the choriocapillaris and choroidal vessels.
  • Autofluorescence photographs and fluorescein angiography provide supplementary diagnostic information by revealing hyper- and hypofluorescent regions of abnormal retinal pigment epithelium and the choriocapillaris.
• Hypogonadotropic hypogonadism usually manifest in the first two decades of life

Common but less frequent features

• Other anterior pituitary hormone deficiencies:
  • Thyroid hormone deficiency may start in infancy, childhood, or adolescence. Onset in infancy may result in intellectual disability and poor growth.
  • Of note, newborn screening for congenital hypothyroidism may detect some newborns with this disorder.
  • Growth hormone deficiency onset may occur in infancy, childhood, or adolescence and may lead to short stature.
• Peripheral neuropathy (usually of axonal type) manifesting as reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting
• Impaired cognitive functioning unrelated to hormone deficiency that may include learning disabilities in children [Yoon et al 2013] and deficits in attention, visuospatial abilities, and recall in adults
• Hair anomalies (long eyelashes, bushy eyebrows, premature graying, or scalp alopecia)

Neuroimaging showing the following:

• Cerebellar atrophy in approximately 90% of all affected individuals [Rainier et al 2011, Yoon et al 2013, Synofzik et al 2014a]
• Small pituitary in 20%-30% of all affected individuals [Yoon et al 2013, Synofzik et al 2014a, Hufnagel et al 2015]
• Thoracic cord atrophy in one individual [Rainier et al 2011]

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of a PNPLA6 disorder is established in a proband with suggestive findings and biallelic PNPLA6 pathogenic (or likely pathogenic) variants in trans configuration identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic PNPLA6 variants of uncertain significance (or of one known PNPLA6 pathogenic variant and one PNPLA6 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of a PNPLA6 disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

In all affected individuals reported to date, features of the PNPLA6 disorder are evident in the first two decades of life [Rainier et al 2011, Yoon et al 2013, Deik et al 2014, Synofzik et al 2014a, Hufnagel et al 2015, Kmoch et al 2015, Tarnutzer et al 2015]. The initial findings include one or several of the following features: gait disturbance, visual impairment due to chorioretinal dystrophy or atrophy, anterior hypopituitarism, delayed puberty/primary amenorrhea. Gait disturbance may precede visual impairment or anterior hypopituitarism; or alternatively, gait disturbance may follow visual impairment or hypopituitarism up to 35 years later [Deik et al 2014]. Although the combination of the three most common findings (gait disturbance, visual impairment, and delayed puberty/primary amenorrhea) is highly indicative of an underlying PNPLA6 disorder, no single feature is specific or obligatory.

Some of these features can occur in certain combinations, presenting in partly distinct/partly overlapping clusters on the phenotypic continuum of the PNPLA6 disorders (see Table 2).

• Boucher-Neuhäuser syndrome (BNS). Cerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism [Boucher & Gibberd 1969]; high predictive value (75%) for an underlying PNPLA6 disorder [Synofzik et al 2014a, Tarnutzer et al 2015]
• Gordon Holmes syndrome (GHS). Cerebellar ataxia, hypogonadotropic hypogonadism, and (to a variable degree) brisk reflexes [Holmes 1907]
• Oliver-McFarlane syndrome (OMCS). Trichomegaly, chorioretinal dystrophy, and congenital or childhood hypopituitarism [Hufnagel et al 2015, Kmoch et al 2015]
• Laurence-Moon syndrome (LMS). Cerebellar ataxia, chorioretinal dystrophy, peripheral neuropathy, spastic paraplegia and congenital or childhood hypopituitarism. One family diagnosed with Laurence-Moon syndrome has been reported to have biallelic pathogenic variants in PNPLA6 [Hufnagel et al 2015]. Several other people with the same phenotypic cluster and biallelic pathogenic variants in PNPLA6 have been reported [Synofzik et al 2014a] and described as having "spastic Boucher-Neuhäuser syndrome," demonstrating the continuum of PNPLA6- associated phenotypic clusters.
• Spastic paraplegia type 39 (SPG39). Upper motor neuron involvement and peripheral neuropathy, and in some cases reduced cognitive functioning and/or cerebellar ataxia [Rainier et al 2008]
• Severe retinal dystrophy with atrophy associated with autism, reported in one child with biallelic pathogenic variants in PNPLA6 [Kmoch et al 2015]. The child had been previously given a diagnosis of Leber congenital amaurosis (LCA). Given the age of the affected individual, it is possible that further features of one of the above clinical diagnoses could develop with time. See Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview.

Given the limited number of individuals reported to date and the lack of longitudinal studies of affected individuals, a more detailed understanding of the natural history of PNPLA6 disorders remains to be determined.

Gait disturbance is due to ataxia, spasticity (with or without paresis), peripheral neuropathy, or a combination thereof. Progression of the gait disturbance varies: more severely affected individuals lose the ability to walk without aid between ages 25 and 50 years and may become wheelchair dependent at this stage [Rainier et al 2011, Synofzik et al 2014a]; less affected individuals are still able to walk unaided at age 54 years [Synofzik et al 2014a].

Dysarthria and dysphagia are recurrent features in PNPLA6 disorders, evolving throughout the disease course in almost all individuals with cerebellar ataxia. Dysarthria appears to present shortly after onset of gait ataxia, with dysphagia following years later, but detailed natural history studies corroborating this clinical impression are still lacking. Both are likely due to cerebellar dysfunction [Tarnutzer et al 2015]. Likewise, urinary urgency appears to be a recurrent feature at least in individuals with PNPLA6-associated ataxias, but a systematic investigation providing detailed evidence for this clinical impression is likewise still lacking.

Peripheral neuropathy (if present) is usually of the axonal motor type, including an additional sensory component (sensorimotor neuropathy) reported to date in only three individuals [Author, unpublished observation]. The motor neuropathy can be associated with severe atrophy of distal muscles, in particular the distal leg and intrinsic hand muscles, starting in the late teens [Rainier et al 2011]. Impairment of the sensory tracts (peripheral sensory neurons, dorsal columns) including diminished vibration sense and touch has been reported in different age groups [Rainier et al 2011, Synofzik et al 2014a, Hufnagel et al 2015, Kmoch et al 2015].

Functional impairment due to upper motor neuron involvement varies: while some affected individuals show only increased reflexes or extensor plantar responses, others have severe spastic paraparesis of the lower extremities [Rainier et al 2011, Synofzik et al 2014a, Hufnagel et al 2015]. Electrophysiologic data available are currently insufficient to determine whether corticospinal tract involvement is axonal (with motor evoked potentials showing almost normal central motor conduction times) or demyelinating (with motor evoked potentials showing severely prolonged central motor conduction times).

Progressive visual impairment, which is less frequent than gait disturbances in the PNPLA6 disorders, is typically due to chorioretinal dystrophy. Initially, these findings (which can present in the first few years of life) include nystagmus, choroidal and retinal pigment atrophy, and bitemporal central visual field defects and blind spot enlargement. In adolescence or adulthood visual acuity is often severely reduced (to perception of hand motion) such that some affected individuals meet the criteria for legal blindness [Synofzik et al 2014a, Hufnagel et al 2015, Kmoch et al 2015, Synofzik et al 2015].

Anterior hypopituitarism manifests either in infancy or childhood (micropenis and cryptorchidism in males, and thyroid and growth hormone deficiency) or in adolescence (hypogonadotropic hypogonadism and growth hormone deficiency) [Hufnagel et al 2015].

• Congenital hypothyroidism and growth hormone deficiency can result in global developmental delay, severe cognitive impairment, and short stature.
• Hypogonadotropic hypogonadism usually becomes manifest during the second decade of life with delayed puberty and lack of secondary sexual characteristics including primary amenorrhea in females, small penis and testes in males, and absent pubic hair and/or breast development.

Cognitive functioning appears to be impaired in many (albeit not all) individuals with a PNPLA6 disorder, including learning disabilities in children [Yoon et al 2013] and deficits in attention, visuospatial abilities, and recall in adults.

The relationship of white matter lesions and cortical and cerebellar degeneration with cognitive disability has not been explored in PNPLA6 disorders; thus, the substrate or network mechanism underlying the cognitive dysfunction is not yet understood.

Genotype-Phenotype Correlations

No obvious genotype-phenotype correlation exists, as the same PNPLA6 pathogenic variant can lead to different presentations (e.g., ataxia plus hypogonadism in one individual, and spastic ataxia in another) and to different degrees and rates of progression of manifestation (e.g., loss of ambulation in an individual age 44 years with a 17-year history of ataxia vs full ambulation in an individual age 42 years with a 36-year history of ataxia) [Synofzik et al 2014a]. Correspondingly, manifestations and disease progression differ not only between but also within families.

Nor does the phenotype appear to depend on either the location of the pathogenic variant or the pathogenic variant type (e.g., missense and frameshift variants) [Synofzik et al 2014a, Hufnagel et al 2015, Kmoch et al 2015].

Prevalence

PNPLA6 disorders are rare in cohorts with unselected neurologic findings. Synofzik et al [2014a] identified two affected persons among 538 unrelated individuals with ataxia, spastic paraplegia, and/or neuropathy.

In contrast, PNPLA6 pathogenic variants are a common cause of Boucher-Neuhäuser syndrome (BNS) and Oliver-McFarlane syndrome (OMCS): individuals in four of six families with BNS and 11 of 12 families with OMCS had biallelic pathogenic variants in PNPLA6 [Synofzik et al 2014a, Hufnagel et al 2015, Kmoch et al 2015]. Given that clinical descriptions of more than 50 index cases with BNS or OMCS have been reported to date, the number of individuals with this phenotype who are found to have biallelic PNPLA6 pathogenic variants is likely to increase in the near future. (For meta-analysis of index cases see Wu et al [2021].)

Disorders with Ataxia

Ataxia with hypergonadotropic hypogonadism due to coenzyme Q₁₀ deficiency [Gironi et al 2004]. In contrast to coenzyme Q₁₀ deficiency, PNPLA6 disorders may present with hypogonadotropic hypogonadism, often also with spasticity, findings not known to be frequently associated with CoQ₁₀ deficiency.

See also Hereditary Ataxia Overview.

Chorioretinal Dystrophy / Leber Congenital Amaurosis (LCA) / Early-Onset Severe Retinal Dystrophy (EOSRD)

Chorioretinal dystrophy / LCA / EOSRD comprises a spectrum of inherited retinal disorders with onset in infancy and early childhood. LCA is characterized by severe visual impairment from birth or the first few months of life, roving eye movements or nystagmus, poor pupillary light responses, oculodigital sign (poking, rubbing, and/or pressing of the eyes), and undetectable or severely abnormal full-field electroretinogram (ERG). EOSRD is characterized by the onset of visual impairment typically after infancy but before age five years, with variably preserved visual acuity and minimally preserved full-field ERG. Persons with PNPLA6 disorders can have evidence of widespread retinal degeneration and vision loss in infancy or throughout childhood and adolescence. Nystagmus is rarely noted in PNPLA6 disorders.

To date, pathogenic variants of 24 genes account for 70%-80% of individuals with LCA/EOSRD. LCA/EOSRD is typically inherited in an autosomal recessive manner; rarely, LCA/EOSRD is inherited in an autosomal dominant manner as a result of a heterozygous pathogenic variant in CRX, OTX2, or IMPDH1.

See also Retinitis Pigmentosa Overview.

Other Types of Disorders

Multisystem mitochondrial diseases with retinopathy. See Mitochondrial Disorders Overview.

Peripheral neuropathies with additional multisystem disease, including retinopathies. See Charcot-Marie-Tooth Hereditary Neuropathy Overview.

Complicated hereditary spastic paraplegias. See Hereditary Spastic Paraplegia Overview.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a PNPLA6 disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

No disease-modifying drug treatment exists for PNPLA6 disorders. Given the great phenotypic variability and broad spectrum of the disorders, management must be tailored to the needs of the individual.

Management by multidisciplinary specialists including a neurologist, ophthalmologist, endocrinologist, physical, occupational, and speech therapists, and neuropsychologist is recommended.

Surveillance

Affected individuals require periodic multidisciplinary reevaluations to assess disease progression and modify treatment strategies (Table 6).

Note that the frequency of recommended surveillance is at the discretion of treating specialists (usually annually or as symptoms change or as medication needs change).

Agents/Circumstances to Avoid

Avoid the following:

• Alcohol
• Obesity
• Inactive, sedentary lifestyle
• Exposure to medications or chemicals that exacerbate neuropathy. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list of medications that are potentially toxic to persons with CMT or a related neuropathy.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Anecdotally, ataxia may sometimes appear for the first time or worsen during pregnancy. Note: While some individuals with ataxia report a worsening of coordination after general anesthesia, no increased risk has been reported specifically with obstetric anesthesia.

Spasticity generally does not change significantly with pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

PNPLA6 disorders are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one PNPLA6 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a PNPLA6 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• 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.
• Although affected sibs usually share most of the same PNPLA6 phenotypic features, some features may be missing or additionally present. For example, within the same family, one sib may have all features of Boucher-Neuhäuser syndrome and another sib may have either spastic ataxia with hypogonadism or chorioretinal dystrophy, but not both. The degree and progression of impairment may also differ among sibs.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with a PNPLA6 disorder are obligate heterozygotes (carriers) for a pathogenic variant in PNPLA6.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a PNPLA6 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the PNPLA6 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the PNPLA6 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for a PNPLA6 disorder are possible. However, given the possibility of intrafamilial variability, the results of such testing do not necessarily predict the phenotype, age of onset, and/or severity of findings.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

PNPLA6 encodes the neuropathy target esterase, which belongs to a protein family of nine patatin-like phospholipase domain-containing proteins. Apart from its phospholipid esterase domain (EST; also sometimes called "patatin domain"), the modular architecture of PNPLA6 protein comprises three CNB domains (CNB1, CNB2, CNB3).

The most important functional domain is the EST domain, which de-esterifies phosphatidylcholine (a major component of biologic membranes) into its constituent fatty acids and glycerophosphocholine [Strickland et al 1995, Atkins et al 2002, van Tienhoven et al 2002, Zaccheo et al 2004]. Glycerophosphocholine is a precursor for the biosynthesis of acetylcholine, a key neurotransmitter involved in mediating cellular signaling in the nervous system. Moreover, it has been suggested that the EST domain has a role in lysophospholipase activity [van Tienhoven et al 2002] and functions in lipid membrane metabolism [Tesson et al 2012].

Current knowledge suggests that biallelic PNPLA6 pathogenic variants cause disease by impairing the capacity of the EST domain to perform one of two functions:

• De-esterify phosphatidylcholine into fatty acids and glycerophosphocholine. (The lack of adequate glycerophosphocholine may disturb development and maintenance of synaptic connections in a variety of neuronal networks.)
• Catalyze 2-arachidonoyl lysophosphatidylinositol, thus disturbing the metabolism of lipid membranes [Synofzik et al 2014a, Hufnagel et al 2015, Kmoch et al 2015].

Mechanism of disease causation. Loss of function

Author Notes

Matthis Synofzik is a professor for translational genomics of neurodegenerative diseases, following the concept to map the full translational pipeline from mapping disease genes via identifying biomarkers to establishing trial-readiness for rare neurologic diseases.
Website

Robert B Hufnagel is a physician-scientist specializing in clinical care, molecular diagnostics, and gene discovery for syndromic ocular disorders.
Website

Stephan Züchner is professor of human genomics, with a dedicated interest of mapping disease genes and genomic variation that is related to disease.
Website

Acknowledgments

This work was supported by the Interdisciplinary Center for Clinical Research IZKF Tübingen (Grant 2191-0-0, to MS, U54NS0657, R01NS075764, R01NS072248); National Eye Institute Intramural Funds (ZIAEY000564, ZIAEY000565); the European Joint Program for Rare Diseases via the PROSPAX consortium (DFG No 441409627 to MS and SZ as an associated partner); the Muscular Dystrophy Association; and the Charcot-Marie-Tooth Association.

Revision History

• 10 June 2021 (bp) Comprehensive update posted live
• 11 June 2015 (me) Comprehensive update posted live
• 9 October 2014 (me) Review posted live
• 29 May 2014 (ms) Original submission

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