Inspired by my colleague's diagnosis of such a patient through whole exome sequencing.
Clinical characteristics.
GLB1-related disorders comprise two phenotypically distinct
lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type
IVB (MPS IVB).
GM1 gangliosidosis includes phenotypes that range from
severe to mild. Type I (infantile) begins before age one year; progressive
central nervous system dysfunction leads to spasticity, deafness, blindness,
and decerebrate rigidity. Life expectancy is two to three years. Type II can be
subdivided into the late-infantile form and juvenile form. Type II, late-infantile
form begins between ages one and three years; life expectancy is five to ten
years. Type II, juvenile form begins between ages three and ten years with
insidious plateauing of motor and cognitive development followed by slow
regression. Type II may or may not include skeletal dysplasia. Type III begins
in the second to third decade with extrapyramidal signs, gait disturbance, and
cardiomyopathy; and can be misidentified as Parkinson disease. Intellectual
impairment is common late in the disease; skeletal involvement includes short
stature, kyphosis, and scoliosis of varying severity.
MPS IVB is characterized by skeletal changes, including
short stature and skeletal dysplasia. Affected children have no distinctive
clinical findings at birth. The severe form is usually apparent between ages
one and three years, and the attenuated form in late childhood or adolescence.
In addition to skeletal involvement, significant morbidity can result from
respiratory compromise, obstructive sleep apnea, valvular heart disease,
hearing impairment, corneal clouding, and spinal cord compression. Intellect is
normal unless spinal cord compression leads to central nervous system
compromise.
Diagnosis/testing.
The diagnosis of GLB1-related disorders is suspected in individuals
with characteristic clinical, neuroimaging, radiographic, and biochemical
findings. The diagnosis is confirmed by either deficiency of β-galactosidase
enzyme activity or biallelic pathogenic variants in GLB1.
Management.
Treatment of manifestations: Best provided by specialists in
biochemical genetics, cardiology, orthopedics, and neurology and therapists
knowledgeable about GLB1-related disorders; surgery is best performed in
centers with surgeons and anesthesiologists experienced in the care of
individuals with lysosomal storage disorders; occupational therapy to optimize
activities of daily living (including adaptive equipment) and physical therapy
to optimize gait and mobility (including orthotics and bracing); early and
ongoing interventions to optimize educational and social outcomes.
For those with GM1 gangliosidosis: Adequate nutrition to
maintain growth; speech therapy to optimize oral motor skills; aggressive
seizure control; routine management of risk of aspiration, risk of chronic urinary
tract infection, and cardiac involvement; when disease is advanced: hospice
services for supportive in-home care.
Prevention of secondary complications: Anesthetic
precautions to anticipate and manage complications relating to skeletal
involvement and airway compromise; routine immunization; bacterial endocarditis
prophylaxis in those with cardiac valvular disease.
http://www.ncbi.nlm.nih.gov/books/NBK164500/
Fantur KM, Wrodnigg TM, Stütz AE, Pabst BM, Paschke E. Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB₁ alleles causing GM1-gangliosidosis and Morquio B disease. J Inherit Metab Dis.2012 May;35(3):495-503.
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Unlike replacement therapy by infusion of exogenous recombinant lysosomal enzymes, pharmacological chaperones aim at a gain of function of endogenous gene products. Deficits resulting from missense mutations may become treatable by small, competitive inhibitors binding to the catalytical site and thus correcting the erroneous conformation of mutant enzymes. This may prevent their premature degradation and normalize intracellular trafficking as well as biological half-life. A major limitation currently arises from the huge number of individual missense mutations and the lack of knowledge on the structural requirements for specific interaction with mutant protein domains. Our previous work on mutations of the β-galactosidase (β-gal) gene, causing GM1 gangliosidosis (GM1) and Morquio B disease (MBD), respectively, characterized clinical phenotypes as well as biosynthesis, intracellular transport and subcellular localization of mutants. We recently identified an effective chaperone, DL-HexDGJ (Methyl 6-{[N(2)-(dansyl)-N(6)-(1,5-dideoxy-D-galactitol-1,5-diyl)- L-lysyl]amino} hexanoate), among a series of N-modified 1-deoxygalactonojirimycin derivatives carrying a dansyl group in its N-acyl moiety. Using novel and flexible synthetic routes, we now report on the effects of two oligofluoroalkyl-derivatives of 1-deoxygalactonojirimycin, Ph(TFM)(2)OHex-DGJ (N-(α,α-di-trifluoromethyl) benzyloxyhexyl-1,5-dideoxy-1,5-imino-D: -galactitol) and (TFM)(3)OHex-DGJ (N-(Nonafluoro-tert-butyloxy)hexyl-1,5-dideoxy-1,5-imino-D: -galactitol) on the β-gal activity of GM1 and MBD fibroblasts. Both compounds are competitive inhibitors and increase the residual enzyme activities up to tenfold over base line activity in GM1 fibroblasts with chaperone-sensitive mutations. Western blots showed that this was due to a normalization of protein transport and intralysosomal maturation. The fact that the novel compounds were effective at very low concentrations (0.5-10 μM) in the cell culture medium as well as their novel chemical character suggest future testing in animal models. This may contribute to new aspects for efficient and personalized small molecule treatment of lysosomal storage diseases.
Muthupalani S, Torres PA, Wang BC, Zeng BJ, Eaton S, Erdelyi I, Ducore R, Maganti R, Keating J, Perry BJ, Tseng FS, Waliszewski N, Pokras M, Causey R, Seger R, March P, Tidwell A, Pfannl R, Seyfried T, Kolodny EH, Alroy J. GM1-gangliosidosis in American black bears: clinical, pathological, biochemical and molecular genetic characterization. Mol Genet Metab. 2014 Apr;111(4):513-21.
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G(M1)-gangliosidosis is a rare progressive neurodegenerative disorder due to an autosomal recessively inherited deficiency of lysosomal β-galactosidase. We have identified seven American black bears (Ursus americanus) found in the Northeast United States suffering from G(M1)-gangliosidosis. This report describes the clinical features, brain MRI, and morphologic, biochemical and molecular genetic findings in the affected bears. Brain lipids were compared with those in the brain of a G(M1)-mouse. The bears presented at ages 10-14 months in poor clinical condition, lethargic, tremulous and ataxic. They continued to decline and were humanely euthanized. The T(2)-weighted MR images of the brain of one bear disclosed white matter hyperintensity. Morphological studies of the brain from five of the bears revealed enlarged neurons with foamy cytoplasm containing granules. Axonal spheroids were present in white matter. Electron microscopic examination revealed lamellated membrane structures within neurons. Cytoplasmic vacuoles were found in the liver, kidneys and chondrocytes and foamy macrophages within the lungs. Acid β-galactosidase activity in cultured skin fibroblasts was only 1-2% of control values. In the brain, ganglioside-bound sialic acid was increased more than 2-fold with G(M1)-ganglioside predominating. G(A1) content was also increased whereas cerebrosides and sulfatides were markedly decreased. The distribution of gangliosides was similar to that in the G(M1)-mouse brain, but the loss of myelin lipids was greater in the brain of the affected bear than in the brain of the G(M1) mouse. Isolated full-length cDNA of the black bear GLB1 gene revealed 86% homology to its human counterpart in nucleotide sequence and 82% in amino acid sequence. GLB1 cDNA from liver tissue of an affected bear contained a homozygous recessive T(1042) to C transition inducing a Tyr348 to His mutation (Y348H) within a highly conserved region of the GLB1 gene. The coincidence of several black bears with G(M1)-gangliosidosis in the same geographic area suggests increased frequency of a founder mutation in this animal population.
Bidchol AM, Dalal A, Trivedi R, Shukla A, Nampoothiri S, Sankar VH, Danda S, Gupta N, Kabra M, Hebbar SA, Bhat RY, Matta D, Ekbote AV, Puri RD, Phadke SR, Gowrishankar K, Aggarwal S, Ranganath P, Sharda S, Kamate M, Datar CA, Bhat K, Kamath N, Shah H, Krishna S, Gopinath PM, Verma IC, Nagarajaram HA, Satyamoorthy K, Girisha KM. Recurrent and novel GLB1 mutations in India. Gene. 2015 Aug 10;567(2):173-81.
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GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in the GLB1 gene, leading to the deficiency of the enzyme β-d-galactosidase. In this study, we report molecular findings in 50 Asian Indian families with GM1 gangliosidosis. We sequenced all the exons and flanking intronic sequences of GLB1 gene. We identified 33 different mutations (20 novel and 13 previously reported). The novel mutations include 12 missense (p.M1?, p.E129Q, p.G134R, p.L236P, p.G262E, p.L297F, p.Y331C, p.G414V, p.K493N, p.L514P, p.P597L, p.T600I), four splicing (c.246-2A>G, c.397-2A>G, c.552+1G>T, c.956-2A>G), three indels (p.R22Qfs*8, p.L24Cfs*47, p.I489Qfs*4) and one nonsense mutation (p.Q452*). Most common mutations identified in this study were c.75+2InsT (14%) and p.L337P (10%). Known mutations accounted for 67% of allele frequency in our cohort of patients, suggesting that these mutations in GLB1 are recurrent across different populations. Twenty three mutations were localized in the TIM barrel domain, β-domain 1 and β-domain 2. In silico sequence and structure analysis of GLB1 reveal that all the novel mutations affect the function and structure of the protein. We hereby report on the largest series of patients with GM1 gangliosidosis and the first from India.
Kwak JE, Son MY, Son YS, Son MJ, Cho YS. Biochemical and molecular
ReplyDeletecharacterization of novel mutations in GLB1 and NEU1 in patient cells with lysosomal storage disorders. Biochem Biophys Res Commun. 2015 Feb 20;457(4):554-60.
Abstract
Lysosomes are cytoplasmic compartments that contain many acid hydrolases and play critical roles in the metabolism of a wide range of macromolecules. Deficiencies in lysosomal enzyme activities cause genetic diseases, called lysosomal storage disorders (LSDs). Many mutations have been identified in the genes responsible for LSDs, and the identification of mutations is required for the accurate molecular diagnoses. Here, we analyzed cell lines that were derived from two different LSDs, GM1 gangliosidosis and sialidosis. GM1 gangliosidosis is caused by mutations in the GLB1 gene that encodes β-galactosidase. A lack of β-galactosidase activity leads to the massive accumulation of GM1 ganglioside, which results in neurodegenerative pathology. Mutations in the NEU1 gene that encodes lysosomal sialidase cause sialidosis. Insufficient activity of lysosomal sialidase progressively increases the accumulation of sialylated molecules, and various clinical symptoms, including mental retardation, appear. We sequenced the entire coding regions of GLB1 and NEU1 in GM1 gangliosidosis and sialidosis patient cells, respectively. We found the novel mutations p.E186A in GLB1 and p.R347Q in NEU1, as well as many other mutations that have been previously reported. We also demonstrated that patient cells containing the novel mutations showed the molecular phenotypes of the corresponding disease. Further structural analysis suggested that these novel mutation sites are highly conserved and important for enzyme activity.