Reply: Complicated hereditary spastic paraplegia due to ATP13A2 mutations: what’s in a name?

Schüle, Rebecca

doi:10.1093/brain/awx282

Cited by 2 publications

(2 citation statements)

References 16 publications

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“…Similar observations have been made for other genes associated with complex phenotypes in recent years [e.g. PNPLA6 (Synofzik et al, 2014a), ATP13A2 (Estrada-Cuzcano et al, 2017), POLR3A (Minnerop et al, 2017), PLA2G6 (Synofzik and Gasser, 2017), and SPG7 (Synofzik and Schule, 2017)] and prompts currently used classification systems to be reconsidered (Marras et al, 2016;Schule, 2017).…”

Section: Discussionsupporting

confidence: 65%

FAHN/SPG35: a narrow phenotypic spectrum across disease classifications

Rattay

Lindig²,

Baets

et al. 2019

Brain

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The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the 'WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers.

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Section: Discussionsupporting

confidence: 65%

FAHN/SPG35: a narrow phenotypic spectrum across disease classifications

Rattay

Lindig²,

Baets

et al. 2019

Brain

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“…Thus, the present 3 sibling case falls in the continuum between the 2 extremities (HSP78 and KRS). 6 , 21 Intrafamilial and interfamilial variations in the clinical presentations associated with ATP13A2 mutation should be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel mutation in ATP13A2 associated with a complicated form of hereditary spastic paraplegia

et al. 2020

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ObjectiveTo establish molecular diagnosis for a family with a complicated form of autosomal recessive hereditary spastic paraplegia with intellectual disability, cognitive decline, psychosis, peripheral neuropathy, upward gaze palsy, and thin corpus callosum (TCC).MethodsPhysical examinations, laboratory tests, structural neuroimaging studies, and exome sequence analysis were carried out.ResultsThe 3 patients exhibited intellectual disability and progressive intellectual decline accompanied by psychiatric symptoms. Gait difficulty with spasticity and pyramidal weakness appeared at the ages of 20s–30s. Brain MRI revealed TCC with atrophic changes in the frontotemporal lobes, caudate nuclei, and cerebellum. Exome sequence analysis revealed a novel homozygous c.2654C>A (p. Ala885Asp) variant in the ATP13A2, a gene responsible for a complicated form of hereditary spastic paraplegia (SPG78), Kufor-Rakeb syndrome, and neuronal ceroid lipofuscinosis. The predominant clinical presentations of the patients include progressive intellectual disability and gait difficulty with spasticity and pyramidal weakness, consistent with the diagnosis of SPG78. Of note, prominent psychiatric symptoms and extrapyramidal signs including rigidity, dystonia, and involuntary movements preceded the spastic paraparesis.ConclusionsOur study further broadens the clinical spectrum associated with ATP13A2 mutations.

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Reply: Complicated hereditary spastic paraplegia due to ATP13A2 mutations: what’s in a name?

Cited by 2 publications

References 16 publications

FAHN/SPG35: a narrow phenotypic spectrum across disease classifications

FAHN/SPG35: a narrow phenotypic spectrum across disease classifications

Identification of a novel mutation in ATP13A2 associated with a complicated form of hereditary spastic paraplegia

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