Oliver–McFarlane syndrome (chorioretinopathy–pituitary dysfunction) with prominent early pituitary dysfunction: differentiation from choroideremia–hypopituitarism

Sönmez, Sibel; Forsyth, Rob; Matthews, Debbie S.F.; Clarke, Michael W.; Splitt, Miranda

doi:10.1097/mcd.0b013e328306a374

Cited by 7 publications

(4 citation statements)

References 3 publications

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“…The latter is an autosomal recessive adult-onset neurodegenerative disorder characterized by progressive cognitive decline, dementia, and variable movement disorders, such as ataxia and chorea. CHH and progressive cerebellar ataxia may also be prominent features in Boucher-Neuhäuser, Oliver-McFarlane, and Lawrence-Moon syndromes ( 56 – 58 ). In contrast with the late-onset neurodegenerative etiology of cerebellar atrophy in these conditions, we show here that PRDM13 mutations disrupt cerebellar development.…”

Section: Discussionmentioning

confidence: 99%

A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

Whittaker¹,

Oleari²,

Gregory³

et al. 2021

Journal of Clinical Investigation

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The positive regulatory (PR) domain containing 13 (PRDM13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis, and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2 + progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13 -deficient mice displayed cerebellar hypoplasia and normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the cooccurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.

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Section: Discussionmentioning

confidence: 99%

A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

Whittaker¹,

Oleari²,

Gregory³

et al. 2021

Journal of Clinical Investigation

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“…Mutations in genes encoding for ubiquitin ligase and deubiquitinase such as RNF216, OTUD4 and STUB1 have been identified in GHS patients (10,(58)(59)(60)(61), linking disordered ubiquitination to neurodegeneration and reproductive dysfunction. PNPLA6 mutations are associated with Boucher-Neuhauser, Oliver McFarlane and Lawrence-Moon syndromes, in which CHH and progressive cerebellar ataxia may be prominent features (62)(63)(64) . In contrast to the late-onset neurodegenerative etiology of cerebellar atrophy in these conditions, we show here that PRDM13 mutations disrupt cerebellar development.…”

Section: Discussionmentioning

confidence: 99%

A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

Whittaker

Oleari

Gregory

et al. 2021

Preprint

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PRDM13 (PR Domain containing 13) is a putative chromatin modifier and transcriptional regulator that functions downstream of the transcription factor PTF1A, which in turn controls GABAergic fate in the spinal cord and neuronal development in the hypothalamus. Here, we report a novel, recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. We investigated the development of hypothalamic neurons and the cerebellum in mice homozygous for a Prdm13 mutant allele. A significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone were observed. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Phenotypically, mice lacking PRDM13 displayed cerebellar hypoplasia, normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of kisspeptin neuron development in the hypothalamus, providing a mechanistic explanation for the co-occurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.

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“…The syndrome may present with varying degrees of neurological symptoms, such as axial and appendicular ataxia, mental retardation, and peripheral neuropathy . Some reports have demonstrated other features, such as alopecia areata and prominent early pituitary dysfunction . There are no brain imaging reports on Oliver‐McFarlane syndrome.…”

Section: Discussionmentioning

confidence: 99%

Neuroimaging Features in Congenital Trichomegaly: The Oliver‐McFarlane Syndrome

Pedroso

Rivero

Miranda

et al. 2013

Journal of Neuroimaging

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A 23-year-old woman presented to our hospital with 9 months history of progressive ataxia, visual loss since childhood due to retinitis pigmentosa and primary amenorrhea. On examination, there were also sparse scalp hair, very long and curled upwards eyelashes and short stature. Oliver-McFarlane syndrome was suspected. Brain MRI disclosed cerebellar atrophy and hyperintense signal in corticospinal tracts on FLAIR and T2-weighted images. Therefore, brain imaging must be thoroughly investigated in patients with suspected Oliver-McFarlane syndrome, in order to determinate whether cerebellar atrophy and hyperintense signal in corticospinal tracts are part of this neurological condition.

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Oliver–McFarlane syndrome (chorioretinopathy–pituitary dysfunction) with prominent early pituitary dysfunction: differentiation from choroideremia–hypopituitarism

Cited by 7 publications

References 3 publications

A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

Neuroimaging Features in Congenital Trichomegaly: The Oliver‐McFarlane Syndrome

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