RESUMEN
We describe a disease encompassing infantile-onset movement disorder (including severe parkinsonism and nonambulation), mood disturbance, autonomic instability, and developmental delay, and we describe evidence supporting its causation by a mutation in SLC18A2 (which encodes vesicular monoamine transporter 2 [VMAT2]). VMAT2 translocates dopamine and serotonin into synaptic vesicles and is essential for motor control, stable mood, and autonomic function. Treatment with levodopa was associated with worsening, whereas treatment with direct dopamine agonists was followed by immediate ambulation, near-complete correction of the movement disorder, and resumption of development.
Asunto(s)
Dopamina/metabolismo , Trastornos del Humor/genética , Trastornos del Movimiento/genética , Mutación , Serotonina/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/genética , Edad de Inicio , Secuencia de Bases , Benzotiazoles/uso terapéutico , Cromosomas Humanos Par 10 , Dopamina/orina , Agonistas de Dopamina/uso terapéutico , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Distonía/genética , Femenino , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Trastornos del Movimiento/tratamiento farmacológico , Trastornos Parkinsonianos/genética , Linaje , Pramipexol , Análisis de Secuencia de ADN , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Síndrome , Proteínas de Transporte Vesicular de Monoaminas/metabolismoRESUMEN
Parkinsonism-dystonia-2 PKDYS2 is an autosomal-recessive disorder, caused by pathogenic biallelic variants in SLC18A2 which encodes the vesicular monoamine transporter (VMAT2) protein. PKDYS2 is a treatable neurotransmitter disease, and the rate of diagnosis of this disorder has increased significantly with the advance of genomic technologies. Our report highlights a novel pathologic variant in one case and a novel finding on MRI Brain, consisting of a normal symmetrical signal intensity in the dorsal brainstem and pons, and it substantiates the significance of genetic testing in the evaluation of children with developmental delays, which influences clinical decisions to enhance patient outcomes.
Asunto(s)
Distonía , Trastornos Distónicos , Trastornos Parkinsonianos , Niño , Humanos , Distonía/genética , Arabia Saudita , Trastornos Distónicos/genética , Trastornos Parkinsonianos/genética , Pruebas GenéticasRESUMEN
SUCLA2 is a component of mitochondrial succinate-CoA ligase and nucleotide diphosphokinase activities. Its absence results in Krebs cycle failure, mitochondrial DNA depletion, and a childhood-fatal encephalomyopathy. We describe a purely neurologic allelic form of the disease consisting of deafness, putamenal hyperintensity on MRI and a myoclonic-dystonic movement disorder unchanging from childhood into, so far, the late fourth decade. We show that succinate supplementation circumvents the Krebs cycle block, but does not correct the neurologic disease. Our patients' Arg407Trp mutation has been reported in children with (yet) no MRI abnormalities. It remains possible that early succinate supplementation could impact the disease.
Asunto(s)
Sordera/genética , Trastornos del Movimiento/genética , Succinato-CoA Ligasas/genética , Sordera/tratamiento farmacológico , Femenino , Humanos , Masculino , Trastornos del Movimiento/tratamiento farmacológico , Mutación Missense , Linaje , Ácido Succínico/uso terapéuticoRESUMEN
Mitochondrial acyl-coenzyme A species are emerging as important sources of protein modification and damage. Succinyl-CoA ligase (SCL) deficiency causes a mitochondrial encephalomyopathy of unknown pathomechanism. Here, we show that succinyl-CoA accumulates in cells derived from patients with recessive mutations in the tricarboxylic acid cycle (TCA) gene succinyl-CoA ligase subunit-ß (SUCLA2), causing global protein hyper-succinylation. Using mass spectrometry, we quantify nearly 1,000 protein succinylation sites on 366 proteins from patient-derived fibroblasts and myotubes. Interestingly, hyper-succinylated proteins are distributed across cellular compartments, and many are known targets of the (NAD+)-dependent desuccinylase SIRT5. To test the contribution of hyper-succinylation to disease progression, we develop a zebrafish model of the SCL deficiency and find that SIRT5 gain-of-function reduces global protein succinylation and improves survival. Thus, increased succinyl-CoA levels contribute to the pathology of SCL deficiency through post-translational modifications.
Asunto(s)
Acilcoenzima A/metabolismo , Enfermedades Mitocondriales/patología , Succinato-CoA Ligasas/genética , Animales , Células Cultivadas , Femenino , Humanos , Lactante , Lisina/metabolismo , Masculino , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Mutación , Proteómica , Sirtuinas/deficiencia , Sirtuinas/genética , Sirtuinas/metabolismo , Succinato-CoA Ligasas/deficiencia , Succinato-CoA Ligasas/metabolismo , Análisis de Supervivencia , Pez CebraRESUMEN
Mis-secreted glycoproteins (LGI1, reelin) are emerging causes of epilepsy. LMAN2L belongs to a glycoprotein secretion chaperone family. One recessive LMAN2L missense mutation predicted to impair the chaperone's interaction with glycoproteins was reported in a family with intellectual disability (ID) and remitting epilepsy. We describe four members of a family with autosomal dominant inheritance of a similar phenotype. We show that they segregate a NM_001142292.1:c.1073delT mutation that eliminates LMAN2L's endoplasmic reticulum retention signal and mislocalizes the protein from that compartment to the plasma membrane. LMAN2L mislocalization, like impaired glycoprotein interaction, disturbs brain development, including generation of developmentally restricted epilepsy.
Asunto(s)
Epilepsia/genética , Discapacidad Intelectual/genética , Lectinas/genética , Proteínas de Transporte de Membrana/genética , Mutación/genética , Niño , Preescolar , Epilepsia/diagnóstico , Humanos , Discapacidad Intelectual/diagnóstico , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Proteína ReelinaRESUMEN
We report a family of Saudi Arabian ancestry with two children presenting with global developmental delay, dystonia, disturbed sleep, and heat intolerance. By genome sequencing, we identified a nonsense variant in the first exon of PI4K2A that was homozygous in both affected individuals and was absent from, or heterozygous in, seven unaffected siblings. PI4K2A is highly expressed in the brain and a mouse model displays a neurological phenotype, implicating PI4K2A as a new disease gene for a neurological disorder.