Mucopolysaccharides also known as Glycosaminoglycans (GAGs), are negatively-charged polysaccharide compounds

Mucopolysaccharides or Glycosaminoglycans, are composed of uronic acid and amino sugar to form heteropolysaccharides which are unbranched. They were first secluded from mucin hence called mucopolysaccharides. They are predominantly present in extracellular compartment.1 Their functions within the body are widespread and determined by their molecular structure. GAGs play a key role in cell signaling, which regulates many biochemical processes. Some of these processes include regulation of cell growth and proliferation, promotion of cell adhesion, anticoagulation, and wound repair. The four primary groups of GAGs are classified based on their core disaccharide units and include heparin/heparan sulfate, chondroitin sulfate/dermatan sulfate, keratan sulfate, and hyaluronic acid.

Properties of glycosaminoglycans

The slippery nature of the mucous and synovial fluid is due to the presence of numerous negative charges on heteropolysaccharide chains making them repulse each other. This is responsible for them to revert to a hydrated state when the compression force is released, hence the pliant nature of synovial fluid and vitreous humor.1

Enzymes involved in glycosaminoglycans degradation

The enzymes are 3 exo – glycosidase (Alpha L- Iduronidase, beta – glucuronidase and beta hexosaminidase) and 2 sulfatase (iduronate -2- sulfatase and N – acetyl galactosamine -4- sulfatase).

Mucopolysaccharidoses

Mucopolysaccharidoses (MPS) is a group of metabolic disorders caused due to deficiency or malfunctioning of lysosomal enzymes required for the degradation of glycosaminoglycans.1 Lysosome is a cell organelle containing various enzymes, which will process and degrade excess heteropolysaccharide chains to their simpler forms, therefore popularly known as a suicide bag. Inadequate or impaired production of these enzymes from lysosomes results in the accumulation of long heteropolysaccharide chains in various tissues. Such large accumulation will eventually cause cellular injury which hampers cell or organ function and its appearance and physical abilities. This condition which is caused due to decreased production or malfunctioning or absence of release of enzymes from lysosome is called lysosomal storage disorder. Based on the deficient enzyme, the catabolism of dermatan sulfate, keratan sulfate, chondroitin sulfate, or hyaluronate may be blocked. There is activation of an alternative pathway and products formed in this alternative pathway are excreted through urine. Each enzyme has unique genes and cDNA encoded which can be used for the production of recombinant enzymes and to identify mutation-causing diseases. Mutations of Mucopolysaccharidosis are heterogeneous, but specific populations have one / a few mutant alleles which are predominant. Except for MPS II which is X-linked, all other Mucopolysaccharidosis are Autosomal Recessive. Most Mucopolysaccharidosis have either point mutations or small changes in genes, whereas large deletion and major rearrangement occur in MPS II.8

MPS I (Hurler, Hurler – Scheie syndrome, Scheie)

MPS I is caused due to deficiency of alpha – L – Iduronidase and is characterized by a wide spectrum of manifestations with Hurler and Scheie syndrome representing extreme ends, whereas Hurler – Scheie syndrome represents intermediate severity. Classification of MPS I into 3 subtypes is based on clinical features, as these subtypes cannot be distinguished based on the diagnostic procedure (Table 1).

MPS I H (Hurler syndrome)

Hurler syndrome occupies the severe end of the clinical spectrum with multisystem involvement in a progressive manner. Diagnosis of a case of Hurler syndrome is usually made between 4-8 months, only umbilical hernia or inguinal hernia may be present at birth and as an infant, they are usually normal as it takes time for accumulation of glycosaminoglycans and cause cell injury. Deceleration of growth is seen between 6-8 months. Developmental delay begins in 12-24 months and is obvious by 2-4 years. Macroglossia first clues about medical recognition. Most children with this syndrome have limited language skills due to hearing loss, developmental delay, and macroglossia. Other features include recurrent ear, nose, and throat infections, coarse facial features, hepatosplenomegaly, and skeletal abnormalities. Most children with Hurler have recurrent upper respiratory tract infections, noisy breathing, and profuse nasal discharge. By the first year of age, corneal clouding becomes apparent. Cardiac complications and respiratory infections are common causes of death. Radiological features include a large skull, with untimely closure of sagittal and lambdoid sutures, thickening of the calvarium, shallow orbit, large – J – shaped sella, and atypical spacing of teeth with a dentigerous cyst, kyphosis with anterior hypoplasia of lumbar vertebrae, diaphyseal enlargement of long bones with irregular metaphyses. Coxa Volga, poorly formed pelvis with the short head of the femur. The ribs have characteristic oar – shape, flat at the sternal end and narrow at the vertebral end. Short phalanges are also seen.

MPS I H/S (Hurler/Scheie syndrome)

The features are intermediate between Hurler and Scheie syndrome. Symptoms start between 3-8 years. Deafness, corneal clouding, and skeletal abnormalities begin early to mid–teens. Micrognathia is a characteristic facial feature in patients with H-S syndrome. Accumulation of glycosaminoglycans in the spinal sheath leads to compression of the cervical cord, but intelligence is normal.

MPS I S (Scheie syndrome)

Scheie syndrome is the mildest form with onset of symptoms after 5 years of age and diagnosis is usually made between 10- 20 years of age. Corneal clouding, skeletal abnormalities, and coarse facial features are seen but stature and intelligence are normal. Skeletal abnormalities are more confined to hands causing claw–hand and carpal tunnel syndrome limiting daily functions. Apart from corneal clouding, glaucoma, and retinal degeneration are also seen causing visual impairment. Accumulation of glycosaminoglycans on valves and chordae tendinae leads to aortic valve stenosis and/or regurgitation.

MPS II (Hunter’s syndrome)

Based on clinical features they are recognized in milder and more severe form. MPS II is transmitted in an X – linked Recessive manner, therefore affected females are rare to find, however, there are few female patients with milder forms and these females could have some additional mutations, preventing the expression of normal alleles (Table 1).

MPS II (Severe form)

The onset of disease is between 2-4 years with progressive neurological deficit. Communicating hydrocephalus exacerbates neurological deficit with increased intracranial pressure after 7 years of age and is apparent by 10- 15 years. Corneas are characteristically clear but retinal detachment can be seen. Involvement of autonomic nervous system causing persistent diarrhea is troublesome to younger patients. Neurological complications are very severe in these patients with deterioration of central nervous system after 7-10 years of age. Cardiac failure due to myocardial thickening, valvular dysfunction, pulmonary hypertension, coronary narrowing is the common cause of death. Other atypical features include ptosis and early onset of seizures.

MPS II (Mild form)

Patients with a milder form of Hunter syndrome have normal intelligence and will survive into adulthood. Clinical features are similar to severe forms of MPS II but at a reduced rate of progression. Corneal papilledema is evident due to the deposition of glycosaminoglycans in the sclera, causing optic nerve compression.

MPS III (Sanfilippo syndrome)

MPS III is divided into four types based on enzyme deficiency which are required for the degradation of heparan sulfate. The enzyme deficiency in type A is N – sulfatase, alpha – N- acetlyglucosaminidase in type B, alpha – glucosaminide acetyltransferase in type C and N – acetylglucosamine – 6 – sulfatase in type D. Clinical features manifest by 2-6 years of age. Hyperactivity with wild behavior, developmental delay, hirsutism, coarse hair, and insomnia is presenting features. Coarse facial features are not prominent and some patients have normal features as adults. Stature is normal and skeletal deformities are mild. Due to poor articulation development of language skills is poor. Severe hearing loss is common. By 16 years of age, there is cortical atrophy leading to severe neurological deficit. Dementia, insomnia, poor attention span, hyperactivity, aggressive behavior, temper tantrums, and profound mental retardation is seen (Table 1).

MPS IV (Morquio syndrome)

The two types of MPS IV TYPE A and TYPE B are caused due to deficiency of enzymes of keratan sulfate metabolism, N- acetlygalactosamine-6–sulfatase and beta–galactosidase respectively. Both types are characterized by skeletal deformities resulting in dwarfism (short stature), with normal intelligence making them unique from other forms of MPS. Patients appear normal at birth. Short stature, genu valgum, kyphosis, and waddling gait with a tendency to fall frequently are early symptoms. Other skeletal abnormalities include platyspondylia, odontoid hypoplasia, hyperlordosis, kyphoscoliosis, ovoid deformities of vertebrae, ulnar deviation at the wrist joint, cubitus valgus, short Phalanges, and osteoporosis. Atlantoaxial subluxation is a unique feature of Morquio syndrome. Extra-skeletal manifestations include recurrent upper respiratory tract infection, small teeth, valvular disease, hearing impairment, and facial features like prognathism, and broad mouth (Table 1).

MPS VI (Maroteaux – Lamy syndrome)

N – acetylgalactosamine deficiency is responsible for MPS VI. Neurological development is normal whereas physical development is impaired. Presentation at birth would be macrocephaly, inguinal hernia, or Umbilical hernia. An obvious clouding of the cornea is seen. Growth is normal for the first few years of life but slowly deteriorate after 6 or 8 years. Restriction of movement at large joints results in a crouched stance. Hepatosplenomegaly is always present. The typical presentation of MPS VI includes patients with short stature, protuberant abdomen, and lumbar lordosis. Radiological changes are macrocephaly, ovoid shape vertebrae, acetabulum hypoplasia, and small flared iliac wings (Table 1).

MPS VII (Sly syndrome)

Patients with the sly syndrome have coarse facial features, protruding sternum, hepatosplenomegaly, umbilical/ inguinal hernia, thoracolumbar gibbus, and mild–moderate mental retardation. Granulocytes showing coarse metachromatic granules are striking. The severe forms of the Sly syndrome are characterized by hydrops foetalis, dysostosis multiplex and features of lysosomal storage disorder. The neonatal form itself is heterogeneous, ranging from death in utero to mild or no hydrops at birth. A review of other pregnancies among mothers of MPS VII patients suggests an increase number of spontaneous abortions. Most patients presenting beyond the neonatal period have increased urinary excretion of glycosaminoglycans. MPS VII patients who present as infants or young children have hepatosplenomegaly, Umbilical/inguinal hernia, short stature, repeated upper respiratory tract infection, pneumonia, and developmental delay.

Symptomatic management

Early initiation of daily exercise, physiotherapy, and counseling helps in improving the quality of life. Dietary modification like restricting sugar, milk, and dairy products will not prevent the progression of disease but has helped people with excessive mucus. Polysomnography can be done to assess the requirements of nighttime oxygen. Tonsillectomy and adenoidectomy can also help to relieve obstructive airway pressure in individuals with obstructive sleep apnea. Shunting surgery helps to drain excess cerebrospinal fluid. Corneal transplantation can be used to tackle corneal clouding to improve vision.9

Bone marrow therapy / Hematopoietic stem cell therapy/ Umbilical cord blood transfusion

Although these procedures are risky with increased mortality and morbidity, if they are done at the right time before significant accumulation in neurons, then the benefits outweigh the risk of causing drastic changes in the natural history of disease and increasing life expectancy.10 Hematopoietic stem cell therapy consists of transferring stem cells from a healthy donor to a patient affected, if the procedure is successful, the donated stem cells begin to multiply and produce all the enzyme which was deficient or malfunctioning in the recipient. Except for skeletal and eye abnormalities, rest all physical abnormalities can be rectified. But coming to neurological outcomes it always shows varied results. Since these procedures are risky extensive counseling of family members is essential before initiation of the procedure.

Enzyme therapy

Nowadays enzyme replacement therapy is gaining more popularity amongst the treatment options available for Mucopolysaccharidosis, due to its ability to alleviate somatic symptoms. Enzyme replacement therapy is based on the principle of the production of recombinant enzymes in continuous human or animal cell lines. These specific enzymes produced by recombinant DNA technology will have mannose – 6- phosphate residue, which will bind to their respective mannose – 6- phosphate receptor present on the cell surface and gain entry into the cell, subsequently executing their action of catabolism on accumulated Glycosaminoglycans. This novel therapy is approved in various countries for patients with moderate to severe grades or for those with complications (Table 7). However, hematopoietic stem cell therapy remained the best choice for patients less than 2 years of age if a suitable donor is available. In such cases, enzyme replacement therapy is usually initiated in the period between diagnosis and transplantation to reduce the mortality and morbidity associated with transplantation.11, 12, 13, 14

Intervention to ease penetration of enzymes across blood-brain barrier

Gene therapy

Gene therapy has derived much attention due to its ability to provide a constant source of deficient enzymes. cDNA of the enzyme prepared by recombinant technique can be given either in vivo or ex vivo.23

The in vivo method includes the injection of a vector containing cDNA systemically or locally, resulting in the expression of enzymes by cells in the target tissue.

The viral vectors used in this technique were procured from adeno- associated viruses (AAV), lentiviruses, or retroviruses (Table 7).

The ex vivo technique involves the transfer of modified autologous cells, which will express the new cDNA deficit of early steps of the lysosomal degradation pathway. Genistein and Rhodamin B are the molecules used for substrate reduction therapies. Genistein is a tyrosine kinase inhibitor that inhibits signal transduction mediated by epidermal growth factor, responsible for expressing glycosaminoglycans synthesizing genes. The antioxidant and anti-inflammatory properties of genistein provide an additional advantage in decreasing proinflammatory cytokines.27 Rhodamin B is a nonspecific inhibitor of glycosaminoglycan synthesis.28

All these new modalities of treatment like direct delivery of enzymes into the cerebrovascular system, gene therapy, substrate reduction therapies, Nano-enabled therapy have shown improvement in neural symptoms to various extents, but all these studies have been conducted on animal models, while studies in human are still in progress.