Pathogenic Variants in GALC Gene Correlate With Late Onset Krabbe Disease and Vision Loss: Case Series and Review of Literature

Krabbe disease (KD) is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene which causes accumulation of the toxic sphingolipid psychosine. GALC variants are associated with increased risk of Lewy body diseases (LBD), an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in KD has pathological similarities to that in LBD, we compared post-mortem KD tissue to that of infant control cases and identified alterations to α-synuclein localisation and expression of modifications associated with LBD. To determine whether α-synuclein in KD displayed pathogenic properties associated with LBD we evaluated its seeding capacity using the real-time quaking-induced conversion assay. Strikingly, seeded aggregation of α-synuclein resulted in the formation of fibrillar aggregates similar to those observed in LBD, confirming the prion-like capacity of KD-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it can result from alterations to biological processes such as sphingolipid homeostasis. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in LBD.

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Atypical Cases of Blowout Fracture with Retained Naso-orbital Foreign Bodies: Case Series and Review of Literature

International Journal of Advanced and Integrated Medical Sciences ◽

10.5005/jp-journals-10050-0015 ◽

2016 ◽

Vol 1 (1) ◽

pp. 38-41

Author(s):

Bhawana Pant ◽

Sanjay Gaur ◽

Tusshar Sharma

Keyword(s):

Foreign Bodies ◽

Vision Loss ◽

Case Series ◽

Review Of Literature ◽

Delay In Diagnosis ◽

Blowout Fracture ◽

The Face ◽

Lateral Posterior ◽

Orbital Blowout Fractures ◽

Orbital Rim

ABSTRACT An orbital blowout fracture is a fracture of any wall of the orbit, including the medial, lateral, posterior, the floor, or the roof. The most common injury site is the floor or the medial wall. Any blow to the face or eye, especially the orbital rim, can cause this injury. Vision threatening complications like permanent diplopia and cosmetically unacceptable enopthalmos make this an important injury to be identified quickly. Here, we present two atypical cases of orbital blowout fractures with retained nasoorbital foreign bodies where mechanism of injury was different but resulted in permanent vision loss due to delay in diagnosis. These type of injuries need prompt management including proper radiological diagnosis and treatment. How to cite this article Pant G, Gaur S, Sharma T. Atypical Cases of Blowout Fracture with Retained Naso-orbital Foreign Bodies: Case Series and Review of Literature. Int J Adv Integ Med Sci 2016;1(1):38-41.

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A single mutation in the GALC gene is responsible for the majority of late onset Krabbe disease patients in the Catania (Sicily, Italy) region

Human Mutation ◽

10.1002/humu.9500 ◽

2007 ◽

Vol 28 (7) ◽

pp. 742-742 ◽

Cited By ~ 23

Author(s):

Willy Lissens ◽

Alessia Arena ◽

Sara Seneca ◽

Mohammad Rafi ◽

Giovanni Sorge ◽

...

Keyword(s):

Late Onset ◽

Krabbe Disease ◽

Single Mutation ◽

Galc Gene

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Clinical Presentations and Genetic Characteristics of Late-Onset MADD Due to ETFDH Mutations in Five Patients: A Case Series

Frontiers in Neurology ◽

10.3389/fneur.2021.747360 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhenchu Tang ◽

Shan Gao ◽

Miao He ◽

Qihua Chen ◽

Jia Fang ◽

...

Keyword(s):

Late Onset ◽

Case Series ◽

Outcome Data ◽

Exercise Intolerance ◽

Lipid Storage Myopathy ◽

Genetic Characteristics ◽

Pathogenic Variants ◽

Clinical Presentations ◽

High Level ◽

Almost All

Background: Late-onset multiple acyl-CoA dehydrogenase deficiency (LO-MADD) describes a curable autosomal recessive genetic disease caused by ETFDH mutations that result in defects in ETF-ubiquinone oxidoreductase. Almost all patients are responsive to riboflavin. This study describes the clinical presentations and genetic characteristics of five LO-MADD patients.Methods: From 2018 to 2021, we collected clinical and genetic data on five patients diagnosed with LO-MADD at our hospital and retrospectively analyzed their clinical characteristics, laboratory examination, electromyography, muscle biopsy, genetic analysis, and outcome data.Results: This study included three males and two females with mean onset age of 37.8 years. Fluctuating exercise intolerance was the most common presentation. Serum creatine kinase (CK) levels were significantly elevated in all patients, and plasma acylcarnitine profiles revealed an increase in long-chain acylcarnitine species in three cases. The urinary organic acid study revealed a high level of hydroxyglutaric acid in all patients. Electrophysiology demonstrated myogenic impairment. Muscle biopsies revealed lipid storage myopathy. Molecular analysis identified nine mutations (three novels and six reported) in ETFDH. Exercise intolerance and muscle weakness were dramatically improved in all patients treated with riboflavin (100 mg) daily following diagnosis.Conclusions: LO-MADD is caused by ETFDH variants and responds well to riboflavin. Three novel ETFDH pathogenic variants were identified, expanding their spectrum in the Chinese population and facilitating future interpretation and analysis of ETFDH mutations.

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GALC mutations in Chinese patients with late-onset Krabbe disease: a case report

10.21203/rs.2.9139/v2 ◽

2019 ◽

Author(s):

Shunzhi Zhuang ◽

Lingen Kong ◽

Caiming Li ◽

Likun Chen ◽

Tingting Zhang

Keyword(s):

Vision Loss ◽

Late Onset ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Molecular Data ◽

Krabbe Disease ◽

Chinese Patients ◽

Case Presentation ◽

Corticospinal Tracts ◽

Magnetic Resonance Imaging Mri

Abstract Background: Krabbe disease (also known as globoid cell leukodystrophy) cause by a deficiency of the enzyme -galactocerebrosidase (galactosylceramidase, GALC). The deficiency of GALC leads to accumulation of galactosylceramide and psychosine, the latter GALC substrate having a potential role in triggering demyelination. Typically, the disease has an infantile onset, with rapid deterioration in the first few months, leading to death before the age of 2 years. The late onset forms (late-infantile, juvenile, and adult forms) are rare with variable clinical outcomes, presenting spastic paraplegia as the main symptom. Case presentation: We recruited a family with two affected individuals. The proband (Patient 1), a 25-year-old male, was presented with slow progressive symptoms, including spastic gait disturbance and vision loss since the 5th year of life. His elder sister (Patient 2), became wheelchair-bound and demented at the age of 22 years. Brain magnetic resonance imaging (MRI) showed increased signal intensity in the white matter along with the involvement of the bilateral corticospinal tracts. GALC deficiency was confirmed by biochemical analysis. DNA sequencing revealed two mutations (c.865G>C: p. G289R and c.136G>T: p. D46Y) in GALC. The clinical characteristics, brain MRI, biochemical and molecular findings led to the diagnosis of Krabbe disease. Conclusion: Clinical and neuroimaged signs, positive enzymatic analysis and molecular data converged to definite diagnosis in this neurodegenerative disease.

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Compound heterozygous pathogenic variants in the GALC gene cause infant-onset Krabbe disease

Translational Pediatrics ◽

10.21037/tp-21-403 ◽

2021 ◽

Vol 0 (0) ◽

pp. 0-0

Author(s):

Xiaoli Zhang ◽

Guohui Niu ◽

Panpan Song ◽

Lijun Wang ◽

Rui Han ◽

...

Keyword(s):

Krabbe Disease ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Galc Gene

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GALC mutations in Chinese patients with late-onset Krabbe disease: a case report

10.21203/rs.2.9139/v1 ◽

2019 ◽

Author(s):

Shunzhi Zhuang ◽

Lingen Kong ◽

Caiming Li ◽

Likun Chen ◽

Tingting Zhang

Keyword(s):

Vision Loss ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Molecular Data ◽

Krabbe Disease ◽

Chinese Patients ◽

Corticospinal Tracts ◽

Magnetic Resonance Imaging Mri

Abstract Background: Krabbe disease (also known as globoid cell leukodystrophy) is an autosomal recessive neurodegenerative disorder caused by a deficiency of the enzyme -galactocerebrosidase (galactosylceramidase, GALC). The deficiency of GALC leads to accumulation of galactosylceramide and psychosine, the latter GALC substrate having a potential role in triggering demyelination. Typically, the disease has an infantile onset, with rapid deterioration in the first few months, leading to death before the age of 2 years. The late onset forms (late-infantile, juvenile, and adult forms) are rare with variable clinical outcomes, presenting spastic paraplegia as the main symptom. Case presentation: We recruited a family with two affected individuals. The proband (Patient 1), a 25-year-old male, was presented with slow progressive spastic gait disturbance and vision loss, suffering since the 5th year of life. His elder sister (Patient 2), became wheelchair-bound and demented at the age of 22 years. Brain magnetic resonance imaging (MRI) showed increased signal intensity in the white matter along with the involvement of the bilateral corticospinal tracts. GALC deficiency was confirmed by biochemical analysis. DNA sequencing revealed two mutations (c.865G>C: p. G289R and c.136G>T: p. D46Y) in GALC. The clinical characteristics, brain MRI, biochemical and molecular findings led to the diagnosis of Krabbe disease. Conclusion: Clinical and neuroimaged signs, positive enzymatic analysis and molecular data converged to definite diagnosis in this neurodegenerative disease.

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Molecular diagnostics of the Krabbe disease in Russian children

L.O. Badalyan Neurological Journal ◽

10.17816/2686-8997-2020-1-01-21-28 ◽

2020 ◽

Vol 1 (1) ◽

pp. 21-28

Author(s):

Alexander A. Pushkov ◽

Nataliya N. Mazanova ◽

Lyudmila M. Kuzenkova ◽

Nataliya V. Zhurkova ◽

Oksana V. Globa ◽

...

Keyword(s):

Enzyme Activity ◽

Molecular Diagnostics ◽

High Efficiency ◽

Molecular Genetic ◽

Krabbe Disease ◽

Control Group ◽

Laboratory Diagnostics ◽

Lysosomal Storage ◽

Pathogenic Variants ◽

Galc Gene

Introduction. Krabbe disease (KD) is the lysosomal storage disease developed due to the decline of the galactocerebrosidase activity associated with mutations in the GALC gene. It leads to the development of oligodendrocytes and lemmocytes (Schwann cells) myelin-forming dysfunction. Nowadays the only possible treatment of KD is hemopoietic cell transplantation which should be performed before the manifestation of any signs of disease. That is why laboratory diagnostics has special significance. The aim of the study. To elaborate the algorithm of a molecular diagnostics of the Krabbe disease (KD) in Russian children. Material and methods. 190 patients were diagnosed for the exclusion of KD during the period from 2012 to 2019. In all cases, there was measured a galactocerebrosidase activity in dry blood spots. In cases with the declined enzyme activity, there was performed a further search of pathogenic variants in the GALC gene. The concentration of glycosyl sphingosine (Lyso-GL1) biomarker was measured in 90 patients included in the study since 2016. Results. The enzyme activity was decreased in all patients in comparison with the control group (0.330.05; 2.950.24 mol/l/h, (p0.001; CI: 95%) in 9 patients. Also, we revealed an increased concentration of Lyso-GL1 biomarker in matched controls (12.501.57 ng/ml; 1.80.33 ng/ml, (p0.005; CI: 95%) in 5 patients. During molecular genetic testing of KD, three novel pathogenic variants of the GALC gene were revealed in 3 out of 9 patients: c.265-2AG, c.1036del and c.2037_2040del. Conclusion. The Lyso-GL1 concentration measurement can be used as an additional diagnostics method of KD. The high efficiency of the presented algorithm for the KD diagnostics in Russian children is presented.

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Newborn Screening for Krabbe Disease—Illinois Experience: Role of Psychosine in Diagnosis of the Disease

International Journal of Neonatal Screening ◽

10.3390/ijns7020024 ◽

2021 ◽

Vol 7 (2) ◽

pp. 24

Author(s):

Khaja Basheeruddin ◽

Rong Shao ◽

Fran Balster ◽

Pearlie Gardley ◽

Laura Ashbaugh

Keyword(s):

Newborn Screening ◽

Late Onset ◽

Population Based ◽

Krabbe Disease ◽

Reference Laboratory ◽

Timely Manner ◽

Second Tier ◽

Galc Gene ◽

Mass Spectrometry Assay

Population-based newborn screening for Krabbe disease was initiated by measurement of galactocerebrosidase (GALC) activity in the state of Illinois in December 2017. Due to the poor specificity of GALC for the diagnosis of Krabbe disease, second-tier testing services were provided to reduce the false positive rates for disease monitoring. Using ultra-pressure liquid chromatography coupled to mass spectrometry assay, a total of 497,147 newborns were screened. In total, 288 infants’ specimens (0.06%) having reduced GALC activity were sent out for second-tier testing to a reference laboratory. All newborns’ reduced GALC specimens were tested for psychosine levels, the presence of a 30-kb deletion and GALC sequencing. The results showed that two infants had elevated psychosine levels (10 and 35 nM) and were referred immediately for evaluation and treatment for Infantile Krabbe disease, and six infants had intermediate PSY levels (≥2 to 5 nM) and are under observation as suspected candidates for late-onset Krabbe disease. In addition, 178 infants had pseudodeficiency alleles, all having psychosine levels < 2.0 nM. Our data show that a high percentage of reduced GALC activity (62%) was due to the presence of pseudodeficiency alleles in the GALC gene. In conclusion, incorporation of psychosine measurements can identify infants with infantile Krabbe disease and probable late-onset Krabbe infants. Furthermore, Krabbe disease screening can be achieved at public health laboratories, and infants with infantile Krabbe disease can be diagnosed in timely manner for better outcome.

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Advances in the Diagnosis and Treatment of Krabbe Disease

International Journal of Neonatal Screening ◽

10.3390/ijns7030057 ◽

2021 ◽

Vol 7 (3) ◽

pp. 57

Author(s):

David A Wenger ◽

Paola Luzi ◽

Mohammad A. Rafi

Keyword(s):

Newborn Screening ◽

Autosomal Recessive ◽

Cultured Cells ◽

Krabbe Disease ◽

Hematopoietic Stem ◽

Pathogenic Variants ◽

Second Tier ◽

Galc Gene ◽

Hydrolysis Of

Krabbe disease is an autosomal recessive leukodystrophy caused by pathogenic variants in the galactocerebrosidase (GALC) gene. GALC activity is needed for the lysosomal hydrolysis of galactosylceramide, an important component of myelin. While most patients are infants, older patients are also diagnosed. Starting in 1970, a diagnosis could be made by measuring GALC activity in leukocytes and cultured cells. After the purification of GALC in 1993, the cDNA and genes were cloned. Over 260 disease-causing variants as well as activity lowering benign variants have been identified. While some pathogenic variants can be considered “severe,” others can be considered “mild.” The combination of alleles determines the type of Krabbe disease a person will have. To identify patients earlier, newborn screening (NBS) has been implemented in several states. Low GALC activity in this screening test may indicate a diagnosis of Krabbe disease. Second tier testing as well as neuro-diagnostic studies may be required to identify those individuals needing immediate treatment. Treatment of pre-symptomatic or mildly symptomatic patients at this time is limited to hematopoietic stem cell transplantation. Treatment studies using the mouse and dog models have shown that combining bone marrow transplantation with intra-venous gene therapy provides the best outcomes in terms of survival, behavior, and preservation of normal myelination in the central and peripheral nervous systems. With earlier diagnosis of patients through newborn screening and advances in treatment, it is hoped that more patients will have a much better quality of life.

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