Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy

AbstractAromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive metabolic disorder resulting from disease-causing pathogenic variants of the dopa decarboxylase (DDC) gene. The neurological features of AADC deficiency include early-onset hypotonia, oculogyric crises, ptosis, dystonia, hypokinesia, impaired development, and autonomic dysfunction. We report a patient with genetically confirmed AADC deficiency presenting with developmental epileptic encephalopathy (DEE). We report a boy with severe intractable epileptic spasms and DEE. The patient was evaluated for cognitive and neurologic impairment. Exome sequencing revealed a homozygous mutation (NM_000790.4:c.121C > A; p.Leu41Met) in the DDC gene. This case expands the clinical spectrum of AADC deficiency and strengthens the association between dopa decarboxylase deficiency and epilepsy. Additional studies are warranted to clarify the mechanisms linking dopa decarboxylase dysfunction to DEE.

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Metachromatic Leucodystrophy: A Case Report

Journal of Nepal Paediatric Society ◽

10.3126/jnps.v31i2.4644 ◽

1970 ◽

Vol 31 (2) ◽

pp. 143-145 ◽

Cited By ~ 1

Author(s):

Subhana Karki ◽

Ganesh Kumar Rai ◽

Raju Kafle

Keyword(s):

Case Report ◽

Autosomal Recessive ◽

Metachromatic Leukodystrophy ◽

Neurodegenerative Disorder ◽

Neurological Symptoms ◽

Arylsulfatase A ◽

Live Births ◽

Metachromatic Leucodystrophy ◽

Deficient Activity

Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative disorder characterized by deficient activity of the enzyme arylsulfatase-A. Deficiency of this enzyme results in intralysosomal storage of sphingolipid cerebroside 3-sulfates (sulfatides), which are abundant in myelin and neurons. A pathological hallmark of MLD is demyelination and neurodegeneration, causing various and ultimately lethal neurological symptoms. Its frequency is estimated to be 1/40,000 live births. The disease encompasses three clinical subtypes: late infantile (40% of the patients with MLD), juvenile (40%), and adult (20%). DOI: 10.3126/jnps.v31i2.4644 J Nep Paedtr Soc 2010;31(2):143-145

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Missense Mutations of the Tissue-Nonspecific Alkaline Phosphatase Gene in Hypophosphatasia

Clinical Chemistry ◽

10.1093/clinchem/38.12.2501 ◽

1992 ◽

Vol 38 (12) ◽

pp. 2501-2505 ◽

Cited By ~ 58

Author(s):

P S Henthorn ◽

M P Whyte

Keyword(s):

Alkaline Phosphatase ◽

Autosomal Recessive ◽

Bone Mineralization ◽

Clinical Severity ◽

Missense Mutations ◽

Gene Encoding ◽

Modes Of Transmission ◽

Pathologic Fractures ◽

Defective Bone ◽

Deficient Activity

Abstract Hypophosphatasia is an inborn error of metabolism that is characterized clinically by defective bone mineralization and biochemically by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) in serum and in tissues. Clinical severity is extremely variable, ranging from death in utero to pathologic fractures first presenting in adulthood. Severe forms of the disease are inherited in an autosomal recessive fashion; the modes of transmission of mild forms are uncertain. Deficiency of TNSALP activity in this condition suggests that mutations in the TNSALP "candidate" gene are the primary defects. This hypothesis was supported in 1988 by the demonstration, in one inbred infant, that an identical missense mutation in both alleles of the gene encoding TNSALP caused lethal hypophosphatasia. Here we summarize the work leading to that discovery and discuss the recent identification of additional missense mutations in the TNSALP gene associated with the entire clinical spectrum of hypophosphatasia.

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Biallelic SCN2A Gene Mutation Causing Early Infantile Epileptic Encephalopathy: Case Report and Review

Journal of Central Nervous System Disease ◽

10.1177/1179573519849938 ◽

2019 ◽

Vol 11 ◽

pp. 117957351984993 ◽

Cited By ~ 2

Author(s):

Shahad AlSaif ◽

Muhammad Umair ◽

Majid Alfadhel

Keyword(s):

Autosomal Recessive ◽

Brain Magnetic Resonance Imaging ◽

Autosomal Recessive Inheritance ◽

Epileptic Encephalopathy ◽

Normal Brain ◽

Infantile Seizures ◽

Gene Defects ◽

Magnetic Resonance Imaging Mri ◽

Neuronal Type

The voltage-gated sodium channel neuronal type 2 alpha subunit (Navα1.2) encoded by the SCN2A gene causes early infantile epileptic encephalopathy (EIEE) inherited in an autosomal dominant manner. Clinically, it has variable presentations, ranging from benign familial infantile seizures (BFIS) to severe EIEE. Diagnosis is achieved through molecular DNA testing of the SCN2A gene. Herein, we report on a 30-month-old Saudi girl who presented on the fourth day of life with EIEE, normal brain magnetic resonance imaging (MRI), normal electroencephalography (EEG), and well-controlled seizures. Genetic investigation revealed a novel homozygous missense mutation (c.5242A > G; p.Asn1748Asp) in the SCN2A gene (NM_001040142.1). This is the first reported autosomal recessive inheritance of a disease allele in the SCN2A and therefore expands the molecular and inheritance spectrum of the SCN2A gene defects.

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Autosomal-Recessive Mutations in AP3B2 , Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2016.10.009 ◽

2016 ◽

Vol 99 (6) ◽

pp. 1368-1376 ◽

Cited By ~ 26

Author(s):

Mirna Assoum ◽

Christophe Philippe ◽

Bertrand Isidor ◽

Laurence Perrin ◽

Periklis Makrythanasis ◽

...

Keyword(s):

Optic Atrophy ◽

Protein Complex ◽

Early Onset ◽

Autosomal Recessive ◽

Epileptic Encephalopathy ◽

Related Protein ◽

Recessive Mutations ◽

Beta 2

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Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2014.06.006 ◽

2014 ◽

Vol 95 (1) ◽

pp. 113-120 ◽

Cited By ~ 66

Author(s):

Julien Thevenon ◽

Mathieu Milh ◽

François Feillet ◽

Judith St-Onge ◽

Yannis Duffourd ◽

...

Keyword(s):

Autosomal Recessive ◽

Epileptic Encephalopathy ◽

Seizure Onset

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Epilepsy and EEG Phenotype of SLC13A5 Citrate Transporter Disorder

Child Neurology Open ◽

10.1177/2329048x20931361 ◽

2020 ◽

Vol 7 ◽

pp. 2329048X2093136

Author(s):

Qian-Zhou Yang ◽

Emily M. Spelbrink ◽

Kimberly L. Nye ◽

Emily R. Hsu ◽

Brenda E. Porter

Keyword(s):

Valproic Acid ◽

Autosomal Recessive ◽

Sodium Citrate ◽

Neonatal Period ◽

Epileptic Encephalopathy ◽

Seizure Freedom ◽

Citrate Transporter ◽

Cognitive Delay ◽

The Face ◽

Multiple Patients

Mutations in the SLC13A5 gene, a sodium citrate cotransporter, cause a rare autosomal recessive epilepsy (EIEE25) that begins during the neonatal period and is associated with motor and cognitive impairment. Patient’s seizure burden, semiology, and electroencephalography (EEG) findings have not been well characterized. Data on 23 patients, 3 months to 29 years of age are reported. Seizures began during the neonatal period in 22 patients. Although seizures are quite severe in many patients later in life, seizure freedom was attainable in a minority of patients. Multiple patients’ chronic seizure management included a few common medications, phenobarbital and valproic acid in particular. Patients EEGs had a relatively well-preserved background for age, even in the face of frequent seizures, little slowing and multiple normal EEGs and do not support an epileptic encephalopathy. Other causes for the motor and cognitive delay beyond epilepsy warrant further study.

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Kohlschütter-Tönz Syndrome With a Novel ROGD1 Variant in 3 Individuals: A Rare Clinical Entity

Journal of Child Neurology ◽

10.1177/08830738211004736 ◽

2021 ◽

pp. 088307382110047

Author(s):

Özlem Akgün-Doğan ◽

Pelin Ozlem Simsek-Kiper ◽

Ekim Taşkıran ◽

Anna Schossig ◽

Gülen Eda Utine ◽

...

Keyword(s):

Autosomal Recessive ◽

Autosomal Recessive Inheritance ◽

Epileptic Encephalopathy ◽

Clinical Findings ◽

Global Developmental Delay ◽

Molecular Characteristics ◽

Long Term Follow Up ◽

Main Components

Kohlschütter-Tönz syndrome (OMIM 226750) is a rare disorder with autosomal recessive inheritance among epileptic encephalopathy syndromes. To date, only 31 Kohlschütter-Tönz syndrome families have been reported in the literature. Early-onset epilepsy, progressive global developmental delay, and amelogenesis imperfecta are the main components of the syndrome. Mutations in ROGDI (MIM 226750) and SLC13A5 (MIM 615905) are responsible for Kohlschütter-Tönz syndrome. Here, we report on the clinical and molecular characteristics of 3 individuals from 2 families, all harboring the same homozygous novel deleterious variant in ROGD1, along with a long-term follow-up and review of the literature. Although the phenotypic features are almost consistent in Kohlschütter-Tönz syndrome, overlooking dental findings and diverse degrees of variability in clinical findings makes diagnosis challenging occasionally. Because there is a limited number of reported patients, identification of new patients and delineation of clinical and molecular findings will increase the awareness of clinicians and enable establishing genotype-phenotype correlations.

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