Case of Multiple Sulfatase Deficiency and Ocular Albinism: A Diagnostic Odyssey

AbstractBackgroundMultiple sulfatase deficiency (MSD) is a rare autosomal recessive inborn error of lysosomal metabolism. The clinical phenotypic spectrum encompasses overlapping features of variable severity and is suggestive of individual single sulfatase deficiencies (i.e., metachromatic leukodystrophy, mucopolysaccharidosis, and X-linked ichthyosis).Case ReportWe describe a 3-year-old male with severe hypotonia, developmental regression and progressive neurodegeneration, coarse facial features, nystagmus (from ocular albinism), and dysmyelinating motor sensory neuropathy. Ethics approval was obtained from the Western University Ontario.ResultsExtensive investigative work-up identified deficiencies of multiple sulfatases: heparan sulfate sulfamidase: 6.5 nmoles/mg/protein/17 hour (reference 25.0-75.0), iduronate-2-sulfate sulfatase: 9 nmol/mg/protein/4 hour (reference 31-110), and arylsulfatase A: 3.8 nmoles/hr/mg protein (reference 22-50). The identification of compound heterozygous pathogenic mutations in the SUMF1 gene c.836 C>T (p.A279V) and c.1045C>T (p.R349W) confirmed the diagnosis of MSD.ConclusionThe complex clinical manifestations of MSD and the unrelated coexistence of ocular albinism as in our case can delay diagnosis. Genetic counselling should be provided to all affected families.

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Expanding the phenotype of SLC12A6-associated sensorimotor neuropathy

BMJ Case Reports ◽

10.1136/bcr-2021-244641 ◽

2021 ◽

Vol 14 (10) ◽

pp. e244641

Author(s):

Petya Bogdanova-Mihaylova ◽

Patricia McNamara ◽

Sarah Burton-Jones ◽

Sinéad M Murphy

Keyword(s):

Corpus Callosum ◽

Autosomal Recessive ◽

Sensory Neuropathy ◽

Rare Condition ◽

Compound Heterozygous ◽

Sensorimotor Neuropathy ◽

Autosomal Recessive Condition ◽

Solute Carrier ◽

Compound Heterozygous Mutations ◽

Clinical Phenotyping

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a rare autosomal recessive condition characterised by early-onset severe progressive neuropathy, variable degrees of ACC and cognitive impairment. Mutations in SLC12A6 (solute carrier family 12, member 6) encoding the K+–Cl- transporter KCC3 have been identified as the genetic cause of HMSN/ACC. We describe fraternal twins with compound heterozygous mutations in SLC12A6 and much milder phenotype than usually described. Neither of our patients requires assistance to walk. The female twin is still running and has a normal intellect. Charcot-Marie-Tooth Examination Score 2 was 8/28 in the brother and 5/28 in the sister. Neurophysiology demonstrated a length-dependent sensorimotor neuropathy. MRI brain showed normal corpus callosum. Genetic analysis revealed compound heterozygous mutations in SLC12A6, including a whole gene deletion. These cases expand the clinical and genetic phenotype of this rare condition and highlight the importance of careful clinical phenotyping.

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Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency: late diagnosis and gender reassignment in a two-year-old child

Problems of Endocrinology ◽

10.14341/probl12749 ◽

2021 ◽

Vol 67 (5) ◽

pp. 53-57

Author(s):

N. Yu. Raygorodskaya ◽

E. P. Novikova ◽

A. N. Tyulpakov ◽

M. A. Kareva ◽

N. A. Nikolaeva ◽

...

Keyword(s):

Autosomal Recessive ◽

Clinical Case ◽

Clinical Manifestations ◽

Autosomal Recessive Disorder ◽

Compound Heterozygous ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Gender Reassignment ◽

And Gender ◽

21 Hydroxylase Deficiency

11β-hydroxylase deficiency is a rare autosomal recessive disorder due to impaired steroidogenesis in the adrenal cortex caused by pathogenic mutations in the CYP11B1 gene. The main clinical manifestations are determined by a deficiency of cortisol, ACTH hyperproduction, excessive androgens secretion and the accumulation of 11-deoxycorticosterone, which leads to the development of arterial hypertension. In the diagnostic search, it is important to take into account the ethnicity of the patient, since the frequency of the disease and the prevalence of mutations differ between ethnic groups. The article presents a clinical case of 11β-hydroxylase deficiency as the result of compound heterozygous mutations in the CYP11B1 gene in a patient of Turkic origin. This case shows the clinical manifestations and the development of complications of 11β-hydroxylase deficiency, the stages of differential diagnosis of patients with 21-hydroxylase deficiency.

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Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): literature review

Neuromuscular Diseases ◽

10.17650/2222-8721-2020-10-3-27-34 ◽

2020 ◽

Vol 10 (3) ◽

pp. 27-34

Author(s):

E. P. Nuzhnyi ◽

S. N. Illarioshkin

Keyword(s):

Early Diagnosis ◽

Cerebellar Ataxia ◽

Molecular Basis ◽

Autosomal Recessive ◽

Clinical Presentation ◽

Clinical Manifestations ◽

Sensory Neuropathy ◽

Genetic Diagnostics ◽

Phenotypic Spectrum ◽

Sensory Polyneuropathy

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a relatively poorly understood autosomal recessive neurodegenerative disease. The molecular basis of CANVAS was discovered only in 2019 and it is associated with the biallelic pentanucleotide AAGGG expansion carriage in the RFC1 gene. With the advent of genetic diagnostics, the understanding of the phenotypic spectrum and variety of clinical manifestations of this disease has expanded, including a combination of cerebellar ataxia and sensory neuropathy, as well as isolated sensory polyneuropathy/ganglionopathy. This review details current information on the etiology, pathogenesis, clinical presentation and diagnosis of CANVAS in order to increase the awareness of practitioners and early diagnosis of this disease.

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Autosomal recessive hyper-IgE syndrome caused by DOCK8 gene mutation with new clinical features: a case report

BMC Neurology ◽

10.1186/s12883-021-02324-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jing Yang ◽

Yan Liu

Keyword(s):

Gene Mutation ◽

Facial Paralysis ◽

Autosomal Recessive ◽

Muscle Tone ◽

Clinical Manifestations ◽

Compound Heterozygous ◽

Serum Ige ◽

Hyper Ige Syndrome ◽

Abnormal Gait ◽

Chinese Girl

Abstract Background Autosomal recessive hyper-IgE syndrome (AR-HIES) caused by DOCK8 gene is a rare immunodeficiency disease, the main clinical manifestations include recurrent Eczema-like rash, skin and lung abscesses, accompanied with increased serum IgE level. Here, we report a 7-year-old Chinese girl with a new clinic features caused by DOCK8 gene mutations. Case presentation A 7-year-old girl was admitted to our hospital because of abnormal walking posture. The clinical manifestations of the patient included abnormal gait, eczema-like rash, fingertip abscess, high muscle tone, and facial paralysis. Among them, high muscle tone and facial paralysis are new clinic features which have not been reported previously. The blood eosinophils and serum IgE levels were significantly increased, and the lymphocyte subsets indicated a decrease of T lymphocytes. The magnetic resonance imaging (MRI) of her brain suggested myelin dysplasia and brain atrophy. Two novel compound heterozygous mutations (c.1868 + 2 T > C and c.5962-2A > G) of DOCK8 gene were identified by whole exome sequencing. By literature review, there are 11 mutations of DOCK8 gene in Chinese AR-HIES patients. Conclusions Two novel splice-site mutations(c.1868 + 2 T > C and c.5962-2A > G) of DOCK8 gene and new clinic features were found in a Chinese girl with AR-HIES, which extends our understanding of DOCK8 gene mutation spectrum and phenotype of AR-HIES in children.

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Papillon-Lefevre Syndrome: Challenge for Periodontal Management

Journal of Nepalese Society of Periodontology and Oral Implantology ◽

10.3126/jnspoi.v3i2.30891 ◽

2019 ◽

Vol 3 (2) ◽

pp. 84-86

Author(s):

Krishna Prasad Lamichhane ◽

Shaili Pradhan ◽

Ranjita Shreshta Gorkhali ◽

Pramod Kumar Koirala

Keyword(s):

Significant Role ◽

Autosomal Recessive ◽

Clinical Manifestations ◽

Autosomal Recessive Disorder ◽

Genetic Mutations ◽

Rare Autosomal Recessive Disorder ◽

Diagnosis And Management ◽

Periodontal Destruction ◽

Palmoplantar Keratosis

Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder associated with rapidly progressing periodontitis leading to premature loss of deciduous and permanent dentition and diffuse palmoplantar keratosis. Immunologic alterations, genetic mutations, and role of bacteria are some aetiologic factors. Patients present with early periodontal destruction, so periodontists play a significant role in diagnosis and management. This paper reports a case of Papillon- Lefevre syndrome with its clinical manifestations and challenges for periodontal management which was diagnosed in dental department.

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Animal Models of Autosomal Recessive Parkinsonism

Biomedicines ◽

10.3390/biomedicines9070812 ◽

2021 ◽

Vol 9 (7) ◽

pp. 812

Author(s):

Guendalina Bastioli ◽

Maria Regoni ◽

Federico Cazzaniga ◽

Chiara Maria Giulia De Luca ◽

Edoardo Bistaffa ◽

...

Keyword(s):

Animal Models ◽

Sleep Disturbances ◽

Autosomal Recessive ◽

Clinical Manifestations ◽

Cognitive Disorders ◽

Dopamine Neurons ◽

Substantia Nigra Pars Compacta ◽

Current Status ◽

Unknown Etiology ◽

Neuron Death

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. The neuropathological hallmark of the disease is the loss of dopamine neurons of the substantia nigra pars compacta. The clinical manifestations of PD are bradykinesia, rigidity, resting tremors and postural instability. PD patients often display non-motor symptoms such as depression, anxiety, weakness, sleep disturbances and cognitive disorders. Although, in 90% of cases, PD has a sporadic onset of unknown etiology, highly penetrant rare genetic mutations in many genes have been linked with typical familial PD. Understanding the mechanisms behind the DA neuron death in these Mendelian forms may help to illuminate the pathogenesis of DA neuron degeneration in the more common forms of PD. A key step in the identification of the molecular pathways underlying DA neuron death, and in the development of therapeutic strategies, is the creation and characterization of animal models that faithfully recapitulate the human disease. In this review, we outline the current status of PD modeling using mouse, rat and non-mammalian models, focusing on animal models for autosomal recessive PD.

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Acute Strokelike Presentation and Long-term Evolution of Diffusion Restriction Pattern in Ethylmalonic Encephalopathy

Journal of Child Neurology ◽

10.1177/08830738211006507 ◽

2021 ◽

pp. 088307382110065

Author(s):

Jaehyung Lim ◽

Brian J. Shayota ◽

Erica Lay ◽

Sarah H. Elsea ◽

Mir Reza Bekheirnia ◽

...

Keyword(s):

Autosomal Recessive ◽

Mitochondrial Disorder ◽

Brain Magnetic Resonance Imaging ◽

Restriction Pattern ◽

Spastic Diplegia ◽

Ethylmalonic Encephalopathy ◽

Developmental Regression ◽

Downstream Effects ◽

Cystic Changes

Ethylmalonic encephalopathy is a rare autosomal recessive mitochondrial disorder caused by pathogenic biallelic variants in the ETHE1 gene. The phenotype of this disease has been attributed to deficiency in the mitochondrial sulfur dioxygenase leading to many downstream effects. Ethylmalonic encephalopathy classically presents with developmental regression, petechiae, acrocyanosis, and chronic diarrhea. The neurologic phenotype includes hypotonia, spastic diplegia, ataxia, and developmental delay. As more patients with this condition are described, the neurologic phenotype continues to expand. Although strokelike episodes or metabolic strokes have been studied in other mitochondrial disorders, they have not been thoroughly reported in this disorder. Herein, we describe 3 patients with ethylmalonic encephalopathy who presented clinically with strokelike episodes and strokelike abnormalities on brain magnetic resonance imaging in the setting of acute illness, and the long-term sequelae with evolution into cystic changes in one of these subjects.

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HINT1 neuropathy in Norway: clinical, genetic and functional profiling

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01746-z ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Silvia Amor-Barris ◽

Helle Høyer ◽

Lin V. Brauteset ◽

Els De Vriendt ◽

Linda Strand ◽

...

Keyword(s):

Axonal Neuropathy ◽

Functional Characterization ◽

Treatment Strategies ◽

Central Nervous System Involvement ◽

Sensory Neuropathy ◽

Muscle Stiffness ◽

Compound Heterozygous ◽

Clinical Genetic ◽

Cellular Models ◽

New Variant

Abstract Background Autosomal recessive axonal neuropathy with neuromyotonia has been linked to loss of functional HINT1. The disease is particularly prevalent in Central and South-East Europe, Turkey and Russia due to the high carrier frequency of the c.110G > C (p.Arg37Pro) founder variant. Results In a cohort of 748 Norwegian patients with suspected peripheral neuropathy, we identified two seemingly unrelated individuals, compound heterozygous for a new variant (c.284G > A, p.Arg95Gln) and the most common pathogenic founder variant (c.110G > C, p.Arg37Pro) in the HINT1 gene. Probands presented with motor greater than sensory neuropathy of various onset, accompanied by muscle stiffness and cramps in the limbs. Furthermore, they displayed non-classical symptoms, including pain in the extremities and signs of central nervous system involvement. Haplotype analysis in both patients revealed a common chromosomal background for p.Arg95Gln; moreover, the variant was identified in Swedish carriers. Functional characterization in HINT1-knockout and patient-derived cellular models, and in HNT1-knockout yeast, suggested that the new variant is deleterious for the function of HINT1 and provided mechanistic insights allowing patient stratification for future treatment strategies. Conclusion Our findings broaden the genetic epidemiology of HINT1-neuropathy and have implications for molecular diagnostics of inherited peripheral neuropathies in Scandinavia.

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Mucopolysaccharidosis III in Mainland China: natural history, clinical and molecular characteristics of 34 patients

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0505 ◽

2020 ◽

Vol 33 (6) ◽

pp. 793-802 ◽

Cited By ~ 1

Author(s):

Weijing Kong ◽

Yan Meng ◽

Liping Zou ◽

Guang Yang ◽

Jing Wang ◽

...

Keyword(s):

Mental Retardation ◽

Autosomal Recessive ◽

Mainland China ◽

Clinical Manifestations ◽

Hereditary Disease ◽

Molecular Characteristics ◽

Speech Delay ◽

Initial Symptoms ◽

Mps Iii ◽

Mps Iiia

AbstractObjectivesSanfilippo syndrome (Mucopolysaccharidosis III, MPS III) is a rare autosomal recessive hereditary disease, which is caused by lysosomal enzyme deficiency. This study was operated to investigate clinical and molecular characteristics of patients with MPS III, which will improve the diagnosis and treatment of MPS III.MethodThirty four patients with MPS III were assessed using clinical evaluation, questionnaire, and scoring system.ResultsAmong the 34 patients, 14 had MPS IIIA, 19 had MPS III B, and one had MPS III C. Speech delay (100%) and intellectual disability (100%) were the most prevalent clinical manifestations in this cohort, followed by hyperactivity (94.12%), hirsutism (91.18%), enlarged head circumference (73.52%), repeated diarrhea (67.64%), sparse teeth (67.64%), and Mongolian spots (64.71%). There were two clinical manifestations that were significantly different between IIIA and IIIB: Hepatosplenomegaly and serrated teeth. The most common initial symptoms at diagnosis were speech delay (52.94%), hyperactivity (35.29%), and mental retardation (29.41%). Genetic analysis of 25 patients was conducted, which identified 12 novel mutations.ConclusionWhen language retardation, mental retardation, and rough facial features occurred, MPS III should be considered. At same time, more examination should be operated, such as examination of changes in cranial magnetic resonance imaging of cerebral cortex atrophy. Hepatosplenomegaly and serrated teeth could be used clinically to preliminarily distinguish IIIA from IIIB.

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Future Prospects of Gene Therapy for Friedreich’s Ataxia

International Journal of Molecular Sciences ◽

10.3390/ijms22041815 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1815 ◽

Cited By ~ 1

Author(s):

Gabriel Ocana-Santero ◽

Javier Díaz-Nido ◽

Saúl Herranz-Martín

Keyword(s):

Gene Therapy ◽

Viral Vectors ◽

Autosomal Recessive ◽

State Of The Art ◽

Friedreich’S Ataxia ◽

Friedreich's Ataxia ◽

First Intron ◽

Progressive Neurodegeneration ◽

Feasible Solutions ◽

Neurogenetic Disease

Friedreich’s ataxia is an autosomal recessive neurogenetic disease that is mainly associated with atrophy of the spinal cord and progressive neurodegeneration in the cerebellum. The disease is caused by a GAA-expansion in the first intron of the frataxin gene leading to a decreased level of frataxin protein, which results in mitochondrial dysfunction. Currently, there is no effective treatment to delay neurodegeneration in Friedreich’s ataxia. A plausible therapeutic approach is gene therapy. Indeed, Friedreich’s ataxia mouse models have been treated with viral vectors en-coding for either FXN or neurotrophins, such as brain-derived neurotrophic factor showing promising results. Thus, gene therapy is increasingly consolidating as one of the most promising therapies. However, several hurdles have to be overcome, including immunotoxicity and pheno-toxicity. We review the state of the art of gene therapy in Friedreich’s ataxia, addressing the main challenges and the most feasible solutions for them.

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