2025 American Academy of Neurology Abstract Website

Objective:

Gordon Holmes first described an autosomal recessive disorder with characteristic coexisting clinical features of progressive ataxia and hypogonadotropic hypogonadism.

Background:

In his original paper he described four patients from a single family, who in their mid-to-late-30s, developed progressive signs and symptoms of cerebellar disease, and lack of secondary sexual characters. Mutations in RNF216, OTUD4, STUB1, PNPLA6, resulting in disruption of ubiquitination process, have been described in the literature.

Design/Methods:

A 26-year-old Caucasian woman with short stature and lack of secondary sexual characteristics (Tanner stage II), sparse hair on axilla and pubic region, primary amenorrhea, who presented with progressively worsening gait and balance that started three years ago. Patient had cerebellar signs including scanning speech, bidirectional gaze-evoked horizontal nystagmus, dysmetria in all extremities, broad based gait and ataxia. She had bilateral lower extremity weakness (MRC 4^-/5) and spasticity in all extremities. Hormone evaluation revealed low serum estradiol, basal LH and FSH. Brain MRI showed pronounced vermis, cerebellar, and superior cerebellar peduncle atrophy.

Results:

The patient had been diagnosed in 8 years before the onset of neurological symptoms with hypogonadotropic hypogonadism and she underwent hormone replacement therapy at that time. The coexisting cerebellar ataxic syndrome, spasticity, and hypogonadotropic hypogonadism suggest a PNPLA6 gene disorder.

Conclusions:

The absence of chorioretinal dystrophy and peripheral neuropathy makes Boucher-Neuhäuser, Oliver-McFarlane, and SPG39 less likely. A clinical diagnosis of Gordon Holmes Syndrome was made, and later confirmed by genetic testing, showing homozygosis of a variant probably pathogenic in PNPLA6 gene (c.1880C>T, p.Ala627Val).