Homozygous mutation of STXBP5L explains an autosomal recessive infantile-onset neurodegenerative disorder

AbstractCongenital glucose-galactose malabsorption (CGGM) is an autosomal recessive disorder originating from an abnormal transporter mechanism in the intestines. It was sourced from a mutation in the SLC5A1 gene, which encodes a sodium-dependent glucose transporter. Here we report a 2-day-old girl with CGGM who presented with severe hypernatremic dehydration due to diarrhea beginning in the first hours of life. Mutation analysis revealed a novel homozygous mutation NM_000343.3 c.127G > A (p.Gly43Arg) in the SLC5A1 gene. Since CGGM can cause fatal diarrhea in the early neonatal period, timely diagnosis of the disease seems to be essential.

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Premature ovarian ageing following heterozygous loss of Senataxin

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa080 ◽

2020 ◽

Author(s):

G N Subramanian ◽

M Lavin ◽

H A Homer

Keyword(s):

Dna Damage ◽

Neurodegenerative Disorder ◽

Dna Helicase ◽

Dna Integrity ◽

Ovarian Activity ◽

Homozygous Mutation ◽

Female Mice ◽

Mating Trial ◽

High Prevalence

Abstract Premature loss of ovarian activity before 40 years of age is known as primary ovarian insufficiency (POI) and occurs in ∼1% of women. A more subtle decline in ovarian activity, known as premature ovarian ageing (POA), occurs in ∼10% of women. Despite the high prevalence of POA, very little is known regarding its genetic causation. Senataxin (SETX) is an RNA/DNA helicase involved in repair of oxidative stress-induced DNA damage. Homozygous mutation of SETX leads to the neurodegenerative disorder, ataxia oculomotor apraxia type 2 (AOA2). There have been reports of POI in AOA2 females suggesting a link between SETX and ovarian ageing. Here, we studied female mice lacking either one (Setx+/−) or both (Setx−/−) copies of SETX over a 12- to 14-month period. We find that DNA damage is increased in oocytes from 8-month-old Setx+/− and Setx−/− females compared with Setx+/+ oocytes leading to a marked reduction in all classes of ovarian follicles at least 4 months earlier than typically occurs in female mice. Furthermore, during a 12-month long mating trial, Setx+/− and Setx−/− females produced significantly fewer pups than Setx+/+ females from 7 months of age onwards. These data show that SETX is critical for preventing POA in mice, likely by preserving DNA integrity in oocytes. Intriguingly, heterozygous Setx loss causes an equally severe impact on ovarian ageing as homozygous Setx loss. Because heterozygous SETX disruption is less likely to produce systemic effects, SETX compromise could underpin some cases of insidious POA.

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Neuropathological Alzheimer’s Disease Lesions in Nasu-Hakola Disease with TREM2 Mutation: Atypical Distribution of Neurofibrillary Changes

Journal of Alzheimer s Disease ◽

10.3233/jad-201085 ◽

2021 ◽

Vol 79 (1) ◽

pp. 25-30

Author(s):

Emanuela Maderna ◽

Silvia Visonà ◽

Vittorio Bolcato ◽

Veronica Redaelli ◽

Paola Caroppo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Autosomal Recessive ◽

Cerebral Atrophy ◽

Autosomal Recessive Disorder ◽

Homozygous Mutation ◽

Neurofibrillary Changes ◽

Axonal Spheroids ◽

Temporal Structures ◽

Cortical Involvement

Nasu-Hakola disease is a rare autosomal recessive disorder associated to mutations in TREM2 and DAP12 genes, neuropathologically characterized by leukoencephalopathy with axonal spheroids. We report the neuropathologic findings of a 51-year-old female with a homozygous mutation (Q33X) of TREM2 gene. Beside severe cerebral atrophy and hallmarks of Nasu-Hakola disease, significant Alzheimer’s disease lesions were present. Neurofibrillary changes showed an atypical topographic distribution being severe at spots in the neocortex while sparing the mesial temporal structures. Our finding suggests that TREM2 genetic defects may favor Alzheimer’s disease pathology with neurofibrillary changes not following the hierarchical staging of cortical involvement identified by Braak.

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Atypical Presentation of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency with Developmental Epileptic Encephalopathy

Journal of Pediatric Epilepsy ◽

10.1055/s-0041-1723768 ◽

2021 ◽

Author(s):

Francesca Marchese ◽

Elena Faedo ◽

Maria Stella Vari ◽

Patrizia Bergonzini ◽

Michele Iacomino ◽

...

Keyword(s):

Amino Acid ◽

Autosomal Recessive ◽

Epileptic Encephalopathy ◽

Dopa Decarboxylase ◽

Acid Decarboxylase ◽

Homozygous Mutation ◽

Amino Acid Decarboxylase ◽

Pathogenic Variants ◽

Neurological Features ◽

Decarboxylase Deficiency

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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A Case of Salt-Wasting Congenital Adrenal Hyperplasia with Triple Homozygous Mutation: Review of Literature

Journal of Pediatric Genetics ◽

10.1055/s-0040-1705110 ◽

2020 ◽

Author(s):

Maria Laura Iezzi ◽

Gaia Varriale ◽

Luca Zagaroli ◽

Stefania Lasorella ◽

Marco Greco ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Autosomal Recessive ◽

Homozygous Mutation ◽

Adrenal Hyperplasia ◽

Phenotype Correlation ◽

Hydroxylase Deficiency ◽

Autosomal Recessive Disorders ◽

Salt Wasting ◽

21 Hydroxylase Deficiency ◽

Recessive Disorders

AbstractCongenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency represents a group of autosomal recessive disorders characterized by impaired cortisol production due to altered upstream steroid conversions, subclassified as classic and nonclassic forms. The genotype–phenotype correlation is possible in the most frequent case but not in all. Despite in literature many mutations are known, there is the possibility of finding a new genetic pattern in patients with CAH.

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Parkin truncating variants result in a loss-of-function phenotype

Scientific Reports ◽

10.1038/s41598-019-52534-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Mariana Santos ◽

Sara Morais ◽

Conceição Pereira ◽

Jorge Sequeiros ◽

Isabel Alonso

Keyword(s):

Autosomal Recessive ◽

Genetic Basis ◽

Neurodegenerative Disorder ◽

Causative Role ◽

Loss Of Function ◽

Portuguese Population ◽

Juvenile Onset ◽

Ubiquitin E3 Ligase ◽

Spanish Populations ◽

Common Neurodegenerative Disorder

Abstract Parkinson disease (PD) is the second most common neurodegenerative disorder. Most cases of PD are sporadic, while 5–10% have a known genetic basis. Variants in the PARK2 gene are the most frequent cause of autosomal recessive juvenile-onset PD. PARK2 encodes parkin, a multi-domain protein that functions as an ubiquitin E3 ligase. Numerous variants spanning all parkin domains have been identified, although the pathogenic relevance for several of those remains unclear. In this study, we aimed to functionally characterize two truncating parkin variants: N52Mfs*29, which is highly prevalent in the Portuguese and Spanish populations, and L358Rfs*77, recently identified in the Portuguese population. Our results indicate that both variants are prematurely degraded by the proteasome, even though proteins levels are still moderate. We also showed that they are aggregation-prone and lead to mislocalized parkin. Interestingly, the L358Rfs*77 variant is mislocalized to the nucleus, which was never reported for parkin variants. While N52Mfs*29 impaired self-ubiquitination activity, the L358Rfs*77 variant seemed to retain it. Both variants, however, fail to ubiquitinate p62 substrate and did not relocalize to depolarized mitochondria. Therefore, we conclude that parkin truncating variants cause loss of parkin function, thus showing their causative role in PD pathogenesis.

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A Novel Homozygous Deletion within the FRY Gene Associated with Nonsyndromic Developmental Delay

Cytogenetic and Genome Research ◽

10.1159/000502598 ◽

2019 ◽

Vol 159 (1) ◽

pp. 19-25 ◽

Cited By ~ 1

Author(s):

Prabakaran Paulraj ◽

Michelle Bosworth ◽

Maria Longhurst ◽

Callie Hornbuckle ◽

Garrett Gotway ◽

...

Keyword(s):

Developmental Delay ◽

Autosomal Recessive ◽

Pediatric Population ◽

Homozygous Deletion ◽

Homozygous Mutation ◽

Biallelic Mutation ◽

Snp Microarray ◽

Low Level

The role of autosomal recessive (AR) variants in clinically heterogeneous conditions such as intellectual disability and developmental delay (ID/DD) has been difficult to uncover. Implication of causative pathogenic AR variants often requires investigation within large and consanguineous families, and/or identifying rare biallelic variants in affected individuals. Furthermore, detection of homozygous gene-level copy number variants during first-line genomic microarray testing in the pediatric population is a rare finding. We describe a 6.7-year-old male patient with ID/DD and a novel homozygous deletion involving the FRY gene identified by genomic SNP microarray. This deletion was observed within a large region of homozygosity on the long arm of chromosome 13 and in a background of increased low-level (2.6%) autosomal homozygosity, consistent with a reported common ancestry in the family. FRY encodes a protein that regulates cell cytoskeletal dynamics, functions in chromosomal alignment in mitosis in vitro, and has been shown to function in the nervous system in vivo. Homozygous mutation of FRY has been previously reported in 2 consanguineous families from studies of autosomal recessive ID in Middle Eastern and Northern African populations. This report provides additional supportive evidence that deleterious biallelic mutation of FRY is associated with ID/DD and illustrates the utility of genomic SNP microarray detection of low-level homozygosity.

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Autosomal recessive polycystic kidney disease: case report of a newborn with rare PKHD1 mutation, rapid renal enlargement and early fatal outcome

Italian Journal of Pediatrics ◽

10.1186/s13052-020-00922-4 ◽

2020 ◽

Vol 46 (1) ◽

Author(s):

Gregorio Serra ◽

Giovanni Corsello ◽

Vincenzo Antona ◽

Maria Michela D’Alessandro ◽

Nicola Cassata ◽

...

Keyword(s):

Respiratory Failure ◽

Kidney Disease ◽

Polycystic Kidney Disease ◽

Autosomal Recessive ◽

Fatal Outcome ◽

Pulmonary Insufficiency ◽

Homozygous Mutation ◽

Polycystic Kidney ◽

Disease Case ◽

Renal Enlargement

Abstract Introduction Autosomal recessive polycystic kidney disease (ARPKD; MIM#263200) is one of the most frequent pediatric renal cystic diseases, with an incidence of 1:20,000. It is caused by mutations of the PKHD1 gene, on chromosome 6p12. The clinical spectrum is highly variable, ranging from late-onset milder forms to severe perinatal manifestations. The management of newborns with severe pulmonary insufficiency is challenging, and causes of early death are sepsis or respiratory failure. In cases of massive renal enlargement, early bilateral nephrectomy and peritoneal dialysis may reduce infant mortality. However, there is no conclusive data on the role of surgery, and decision-making is driven by patient’s clinical condition and expertise of the center. Patient presentation We hereby describe a preterm female newborn with perinatal, rapid and bilateral, abnormal growth of both kidneys, respiratory failure and initial signs of liver disease. She was subsequently confirmed to be affected by a rare and severe homozygous mutation of the PKHD1 gene, inherited from both her consanguineous parents. Our patient died 78 days after birth, due to a fungal sepsis which worsened her respiratory insufficiency. Conclusions This patient report shows some of the clinical and ethical issues of neonatal ARPKD, and the need of multidisciplinary approach and good communication with the family. Target next generation sequencing (NGS) techniques may guide and support clinicians, as well as guarantee to these patients the most appropriate clinical management, avoiding unnecessary and/or disproportionate treatments.

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Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Recessive Neurodegenerative Disorder Linked to Brain Hypomyelination and Leukodystrophy

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2008.05.016 ◽

2008 ◽

Vol 83 (1) ◽

pp. 30-42 ◽

Cited By ~ 137

Author(s):

Daniella Magen ◽

Costa Georgopoulos ◽

Peter Bross ◽

Debbie Ang ◽

Yardena Segev ◽

...

Keyword(s):

Autosomal Recessive ◽

Neurodegenerative Disorder

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Case Report: Expanding the Genetic and Phenotypic Spectrum of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Frontiers in Genetics ◽

10.3389/fgene.2020.585136 ◽

2020 ◽

Vol 11 ◽

Author(s):

Parham Habibzadeh ◽

Zahra Tabatabaei ◽

Soroor Inaloo ◽

Muhammad Mahdi Nashatizadeh ◽

Matthis Synofzik ◽

...

Keyword(s):

Case Report ◽

Clinical Features ◽

Autosomal Recessive ◽

Neurodegenerative Disorder ◽

Deletion Mutation ◽

Sensorimotor Neuropathy ◽

Spastic Ataxia ◽

Phenotypic Spectrum ◽

Iranian Family ◽

Biallelic Mutations

Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is a rare neurodegenerative disorder caused by biallelic mutations in the SACS gene. Once thought to be limited to Charlevoix–Saguenay region of Quebec, recent evidence has indicated that this disorder is present worldwide. It is classically characterized by the triad of ataxia, pyramidal involvement, and axonal-demyelinating sensorimotor neuropathy. However, diverse clinical features have been reported to be associated with this disorder. In this report, we present the first Iranian family affected by ARSACS with unique clinical features (mirror movements, hypokinesia/bradykinesia, and rigidity) harboring a novel deletion mutation in the SACS gene. Our findings expand the genetic and phenotypic spectrum of this disorder.

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