Paula and Bobby
Parents of Lillie
Mucopolysaccharidosis, Type IIIB
What is Mucopolysaccharidosis, Type IIIB?
It is a subtype of Mucopolysaccharidosis, Type III. There are four subtypes of this form of the syndrome. Known as a form of childhood dementia the syndrome causes brain damage that is eventually fatal.
Type B is the second most common subtype, after Type A. Except in some Southern European countries where it is the most common subtype.
This syndrome is also known as:
MPS IIIA-D Mps Iiib MPSIII Mucopolysaccharidosis III Mucopolysaccharidosis type III N-acetyl-alpha-d-glucosaminidase Deficiency Naglu Deficiency Sanfilippo Syndrome B
What gene changes cause Mucopolysaccharidosis, Type IIIB?
Changes in the NAGLU gene are responsible for causing the syndrome. It is inherited in an autosomal recessive manner.
Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.
What are the main symptoms of Mucopolysaccharidosis, Type IIIB?
Symptoms of the syndrome do not usually present at birth. One of the first symptoms recognised is developmental delay which is usually identified in early childhood and before the age of 6. From this age the symptoms become more severe, and intellectual ability starts to decline. Behavioral issues, including hyperactivity, are also a major symptom and often one of the first identified. Sleeping issues are also common. Affected individuals will also experience speech delay which gets progressively worse with age.
Physical features of the syndrome include coarse hair, excessive hair growth, coarse facial features, and hearing and vision loss. Enlarged organs such as the liver and/or spleen and hernias are also features of the syndrome.
Life expectancy can be varied, ranting from childhood, to early adolescence or early adulthood
Possible clinical traits/features:
Hyperactivity, Hirsutism, Hearing impairment, Hepatomegaly, Heparan sulfate excretion in urine, Joint stiffness, Intellectual disability, Seizure, Thickened ribs, Autosomal recessive inheritance, Ovoid thoracolumbar vertebrae, Synophrys, Progressive neurologic deterioration, Sleep disturbance, Recurrent upper respiratory tract infections, Splenomegaly, Juvenile onset, Dense calvaria, Coarse hair, Coarse facial features, Diarrhea, Dysostosis multiplex, Asymmetric septal hypertrophy, Aggressive behavior, Cardiomegaly
How does someone get tested for Mucopolysaccharidosis, Type IIIB?
The initial testing for Mucopolysaccharidosis, Type IIIB can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Mucopolysaccharidosis, Type IIIB
Mucopolysaccharidosis type III is a group of lysosomal storage diseases categorized by disrupted heparan sulfate degradation. The main clinical features are central nervous system degeneration, intellectual disability, behavioral disturbance, and mildly coarse facial features. Mucopolysaccharidosis type IIIA, which is caused by mutations in the SGSH gene, typically appears earlier in life and progresses more rapidly. This can be the most difficult form of mucopolysaccharidosis to diagnose because of the relatively mild dysmorphic features and the absence of mucopolysaccharides in the urine by some screening tests. Intellectual deterioration may be the presenting feature (Ozand et al., 1994), although mild coarsening of the facial features, hirsutism, or minimal signs of dysostosis multiplex may be noted. Growth can be mildly retarded, although increased growth with advanced bone age can occur early on. Precocious puberty can be a feature (Concolino et al., 2008). Recurrent diarrhea might be part of the presenting symptoms. Thickening of the mitral valve can be severe. Corneal clouding and hepatosplenomegaly are usually absent. Behavior is extremely difficult to manage, as there are aggression and hyperactivity. Cleary and Wraith (1993) provide a good review of the behavioral aspects and management.
Biochemically, the defect is in the breakdown of heparan sulphate. Four separate enzyme defects have been recognized, giving types A, B, C, and D.
Scott et al., (1995) cloned the sulphamidase gene and identified mutations in Sanfilippo A patients. Blanch et al., (1997), Yogalingam and Hopwood (2001), and Lee-Chen et al., (2002) reported further mutations in Sanfilippo syndrome type A. Some patients with type A present with milder disease in adulthood (Lindor et al., 1994, Miyazaki et al., 2002, Gabrielli et al., (2005). This latter patient had an R206P mutation.
Zhao et al., (1996) cloned the gene for type B. Genotype/phenotype correlations for type B mutations were reported by Zhao et al., (1998) and Schmidtchen et al., (1998). Further mutations were reported by Beesley et al., (1998), Bunge et al., (1999), Tessitore et al., (2000), and Yogalingam and Hopwood (2001).
In a cohort of 18 Sanfilippo B families reported by Beesley et al., (2005), 94% had mutations.
Nelson et al., (2003) found the incidence in Western Australia to be approximately 1 in 58,000.
Ramaswami et al., (1996) reported a case with type IIIB who presented with a transient renal tubular dysfunction at 10 weeks of age.
Zafeiriou et al., (2001) reported brain MRI findings, which can include white matter abnormalities, cortical atrophy, and ventricular enlargement.
Fraser et al., (2002) review sleep disturbance and the treatment options.
Tylki-Syzmanska et al., (2002) report three cases and provide a good review of the literature.
Van Hove et al., (2003) reported a 53-year-old woman with no neurological abnormalities but a hypertrophic cardiomyopathy. Residual heparan sulphaminidase activity was demonstrated in leukocytes and fibroblasts.
Hrebicek et al., (2006) and Fan et al., (2006) reported TMEM76 (HGSNAT) mutations in Sanfilippo type C. This codes for a transmembrane protein.
The gene for type IIIC has also now been cloned (Mok et al., 2003; Ausseil et al., 2004) and mutations found in the gene (GNS) encoding N-acetylglucosamine-6-sulfatase.
Berger-Plantiga et al., (2004) reported two adult sisters with type IIIC, who demented and had a retinitis pigmentosa.
Beesley et al., (2003) reported a homozygous mutation in the type D gene in the son of consanguineous parents, and Beesley et al., (2007) reported two Italian families with homozygous mutations.
Further mutations were reported by Jansen et al., (2007) in type D.
Valstar et. al. (2010) reported 12 patients with biallelic mutations in the GNS gene. Clinical characteristics were similar to that reported previously of all MPS III patients and included developmental delay, speech delay, behavioural problems and coarse facies.
Hu et. al., (2016) described a pair of siblings with homozygous mutation in the HGSNAT gene and clinical characteristics of Sanfilippo type C. Both developed Klüver-Bucy syndrome manifested as hyperorality, hypersexuality, prosopagnosia (face blindness), visual-sensory agnosia (psychic blindness), and hypermetamorphosis.
Wolfenden et. al., (2017) made a systematic review of symptoms of autism spectrum disorders in patients with MPS III. Data from 16 studies were included. There was an evidence that ASD-like symptoms were present in individuals with MPS III. Speech, language and communication difficulties were consistently reported but repetitive and restricted behaviour was less common.
Lavery et. al., (2017) analyzed the cause of death of patients with MPS III. In total, 84 patients for type A, 24 of type B and 5 of type c were included. Types A and B showed statistically significant improvement in life expectancy over the years. And mean age of death was greater for type C over B, and type B over A. Primary cause of death of types A and B was pneumonia.
A male patient with mild initial symptoms and hyperckemia was reported by Kartal et. al., (2017). The diagnosis of Sanfilippo was suspected by findings of dysostosis multiplex in radiological studies and later confirmed by null activity of the enzyme sulfamidase activity in leukocytes.
Knottnerus et. al., (2017) proposed a method for predicting phenotypic severity in MPS IIIA patients measuring residual SGSH activity at 30°C. Phenotypic severity correlated with the potential to increase sulfamidase activity in fibroblasts cultured at 30°C, allowing distinction between patients with rapidly progressing and slowly progressing phenotypes.
Tardieu et. al. (2017) described the clinical course of four patients with MPS III type B who underwent intracerebral gene therapy (intraparenchymal deposits of a recombinant adeno-associated viral vector encoding human NAGLU gene plus immunosuppressive therapy). Neurocognitive progression improved in all patients compared to natural history.
Zeng et. al. (2017) reported an additional patient with biallelic NAGLU gene mutations. Clinical characteristics included speech delay, rude behaviour, protruded tongue, slightly flat fifth lumbar vertebra, and cognitive decline. No typical signs associated with MPS IIIB such as coarse facies, hepatomegaly, or skeletal findings were documented.
Velasco et. al. (2017), described five interrelated patients with homozygous missense mutations in the HGSNAT gene. An earlier presentation of some neurological symptoms (epilepsy, loss of language, loss of ambulation) was observed.
* This information is courtesy of the L M D.
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