Paula and Bobby
Parents of Lillie
Mucopolysaccharidosis Type IIIA (MPS3A)
What is Mucopolysaccharidosis Type IIIA (MPS3A)?
Mucopolysaccharidosis Type IIIA is a rare genetic metabolic disorder. It is often also referred to as Sanfilippo syndrome.
The disease usually presents itself post infancy in early childhood, and a major symptom is a developmental regression.
The disease is progressive and affects, over time, the brain and spinal cord.
Heparan Sulfate Sulfatase Deficiency Mps Iiia MPS IIIA-D MPSIII Mucopolysaccharidosis III Mucopolysaccharidosis type III Sanfilippo Syndrome A Sulfamidase Deficiency
What gene changes cause Mucopolysaccharidosis Type IIIA (MPS3A)?
The syndrome caused by mutations on the following genes: GNS, HGSNAT, NAGLV, SGSH.
The syndrome is a lysosomal storage disease, affecting the body's ability to break down the large sugar molecules known as glycosaminoglycans. The buildup of these molecules in the body tissue triggers the symptoms of the syndrome. It is inherited in an autosomal recessive pattern.
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 IIIA (MPS3A)?
Symptoms of the syndrome included delayed and regressive speech development and behavior problems. Many individuals are also diagnosed with an autism spectrum disorder. Other symptoms may include issues with sleep, seizures, chronic diarrhea, and an umbilical or inguinal hernia. A slightly enlarged liver is also often a symptom.
Physical features of the syndrome include a large head, and issues with both hearing and vision.
Possible clinical traits/features:
Autosomal recessive inheritance, Ovoid thoracolumbar vertebrae, Thickened ribs, Seizure, Recurrent upper respiratory tract infections, Sleep disturbance, Splenomegaly, Synophrys, Intellectual disability, Joint stiffness, Asymmetric septal hypertrophy, Coarse hair, Coarse facial features, Dysostosis multiplex, Diarrhea, Dense calvaria, Growth abnormality, Hepatomegaly, Heparan sulfate excretion in urine, Hearing impairment, Hirsutism, Hyperactivity
How does someone get tested for Mucopolysaccharidosis Type IIIA (MPS3A)?
The initial testing for Mucopolysaccharidosis Type IIIA 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 IIIA
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.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]
What is FDNA Telehealth?
FDNA Telehealth is a leading digital health company that provides faster access to accurate genetic analysis.
With a hospital technology recommended by leading geneticists, our unique platform connects patients with genetic experts to answer their most pressing questions and clarify any concerns they may have about their symptoms.
Benefits of FDNA Telehealth
Our platform is currently used by over 70% of geneticists and has been used to diagnose over 250,000 patients worldwide.
FDNA Telehealth provides facial analysis and screening in minutes, followed by fast access to genetic counselors and geneticists.
Ease of Use
Our seamless process begins with an initial online diagnosis by a genetic counselor and follows by consultations with geneticists and genetic testing.
Accuracy & Precision
Advanced artificial intelligence (AI) capabilities and technology with a 90% accuracy rate for a more accurate genetic analysis.
Faster access to genetic counselors, geneticists, genetic testing, and a diagnosis. As fast as within 24 hours if required. Save time and money.
Privacy & Security
We guarantee the utmost protection of all images and patient information. Your data is always safe, secure, and encrypted.