Progressive cerebellocerebral atrophy: a new syndrome with microcephaly, mental retardation, and spastic quadriplegia

Ben‐Zeev, Bruria

doi:10.1136/jmg.40.8.e96

Cited by 53 publications

(43 citation statements)

References 20 publications

(18 reference statements)

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“…SEPSECS mutations were previously described in a single report, underlying progressive cerebellocerebral atrophy with profound mental retardation, progressive microcephaly, severe spasticity, and myoclonic or generalized tonic-clonic seizures, later classified as pontocerebellar hypoplasia type 2D (PCH2D) (MIM 613811). 12,14 The MRI findings of progressive cerebellar atrophy, followed by cerebral atrophy involving both white and gray matter, mimicked the findings in our patients. In contrast to a normal metabolic profile of patients with PCH2D, 12 our patients had lactacidemia, and they also presented with axonal neuropathy.…”

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confidence: 83%

Selenoprotein biosynthesis defect causes progressive encephalopathy with elevated lactate

et al. 2015

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Objective: We aimed to decipher the molecular genetic basis of disease in a cohort of children with a uniform clinical presentation of neonatal irritability, spastic or dystonic quadriplegia, virtually absent psychomotor development, axonal neuropathy, and elevated blood/CSF lactate. Methods:We performed whole-exome sequencing of blood DNA from the index patients. Detected compound heterozygous mutations were confirmed by Sanger sequencing. Structural predictions and a bacterial activity assay were performed to evaluate the functional consequences of the mutations. Mass spectrometry, Western blotting, and protein oxidation detection were used to analyze the effects of selenoprotein deficiency.Results: Neuropathology indicated laminar necrosis and severe loss of myelin, with neuron loss and astrogliosis. In 3 families, we identified a missense (p.Thr325Ser) and a nonsense (p.Tyr429*) mutation in SEPSECS, encoding the O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase, which was previously associated with progressive cerebellocerebral atrophy. We show that the mutations do not completely abolish the activity of SEPSECS, but lead to decreased selenoprotein levels, with demonstrated increase in oxidative protein damage in the patient brain. Conclusions:These results extend the phenotypes caused by defective selenocysteine biosynthesis, and suggest SEPSECS as a candidate gene for progressive encephalopathies with lactate elevation. Neurology ® 2015;85:306-315 GLOSSARY PCH2D 5 pontocerebellar hypoplasia type 2D; PEHO 5 progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy; RC 5 respiratory chain; SRM-MS 5 selected reaction monitoring-mass spectrometry; T 4 5 thyroxine; tRNA 5 transfer RNA; TSH 5 thyroid-stimulating hormone; T 3 5 triiodothyronine.Mitochondrial dysfunction is a frequent cause of childhood encephalopathy. Besides the typical multisystemic disorders, an increasing number of mitochondrial defects are shown to cause a CNS-specific phenotype.1-5 Lactate elevation raises suspicion of mitochondrial involvement and may be observed even in encephalopathies in which muscle biopsies show normal mitochondrial respiratory chain (RC) function. [1][2][3]6 Within our cohort of pediatric patients, we identified patients with an undefined cause of cerebellocerebral atrophy, seizures, severe spasticity, and axonal neuropathy with lactate elevation. We report that despite many of the clinical and neuropathologic signs pointing toward mitochondrial impairment, the patients had novel mutations in the SEPSECS gene, which functions in cytoplasmic transfer RNA (tRNA)-charging in the selenoprotein biosynthesis pathway. We describe the uniform clinical, neuroradiologic, and neuropathologic features of this entity and a detailed mutation *These authors contributed equally to this work.From the

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confidence: 83%

Selenoprotein biosynthesis defect causes progressive encephalopathy with elevated lactate

et al. 2015

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“…Homozygous or compound heterozygous mutations in other Vps genes, VPS33B and VPS53, were previously associated with arthrogryposis-renal dysfunction-cholestasis syndrome (ARCS) type 1 (OMIM 208085) and pontocerebellar hypoplasia type 2E (PCH2E) (OMIM 615851), respectively (50,51). Joint contractures and cerebellar anomalies were previously defined in patients with PCH2E (52). Moreover, VPS8 has close interactions with VPS33B and VPS53, as well as VIPAS39 ( Figure 5C), and mutations of VIPAS39 were associated with ARCS type 2 (OMIM 613404) (53).…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Bayram

Karaca

Akdemir

et al. 2016

Journal of Clinical Investigation

111

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“…PCCA is an autosomal recessive inherited disorder initially described in non-consanguineous families of Jewish Sephardic origin [113]. Patients present with profound mental retardation, progressive microcephaly, and severe spasticity often associated with generalized tonicclonic or myoclonic seizures.…”

Section: Selenocysteine Synthase (Sepsecs)mentioning

confidence: 99%

Post-Transcriptional Control of Selenoprotein Biosynthesis

Seeher

Mahdi²,

Schweizer³

2012

CPPS

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Selenoproteins are defined as proteins containing the 21st proteinogenic amino acid, selenocysteine (Sec). Sec is encoded by UGA (STOP) codons which are re-coded to Sec by the presence of a selenocysteine insertion sequence (SECIS) element in the 3'-untranslated region of selenoprotein mRNAs. The SECIS element is bound by several proteins, including SECIS-binding protein 2 (SBP2). Translation of selenoproteins critically depends on the integrity of the SECIS element - SBP2 interaction. Mutations in a SECIS element can abrogate expression of the respective selenoprotein. Mutations in SBP2 impinge on biosynthesis of a subset of selenoproteins and lead to a syndrome including hormonal, neurological, immunological symptoms as well as myopathy. Several other RNA-binding proteins are involved in selenoprotein translation and mediate the hierarchical response of selenoproteins to selenium deficiency. Global inhibition of selenoprotein translation is lethal in the mouse and hypomorphic mutations in selenocysteine synthase in humans leads to Progressive Cerebello Cerebral Atrophy, a neurodevelopmental and neurodegenerative disease in pediatric patients.

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Progressive cerebellocerebral atrophy: a new syndrome with microcephaly, mental retardation, and spastic quadriplegia

Cited by 53 publications

References 20 publications

Selenoprotein biosynthesis defect causes progressive encephalopathy with elevated lactate

Selenoprotein biosynthesis defect causes progressive encephalopathy with elevated lactate

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Post-Transcriptional Control of Selenoprotein Biosynthesis

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