Clinical Guidance
In all affected individuals reported to date, features of the PNPLA6 disorder are evident in the first two decades of life [, , , , , , ]. 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 . 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 . • Boucher-Neuhuser syndrome (BNS). Cerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism ; high predictive value (75%) for an underlying PNPLA6 disorder • Gordon Holmes syndrome (GHS). Cerebellar ataxia, hypogonadotropic hypogonadism, and (to a variable degree) brisk reflexes • Oliver-McFarlane syndrome (OMCS). Trichomegaly, chorioretinal dystrophy, and congenital or childhood hypopituitarism • 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 . Several other people with the same phenotypic cluster and biallelic pathogenic variants in PNPLA6 have been reported and described as having "spastic Boucher-Neuhuser 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 • Severe retinal dystrophy with atrophy associated with autism, reported in one child with biallelic pathogenic variants in PNPLA6 . 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. Table 2. PNPLA6 Disorders: Comparison of Phenotypic Clusters by Select Features Phenotypic Feature | PNPLA6 Disorder
BNS | GHS | OMCS | LMS | SPG39 |
|---|
Cerebellar ataxia | + | + | + | ± Peripheral neuropathy |
± Chorioretinal dystrophy | + | — | — | — |
+ | + | — | — | — |
Hypogonadotropic hypogonadism | |
Source: GeneReviews — "PNPLA6 Disorders"
