Multiple sulfatase deficiency

Alternate Names

MSD; Juvenile sulfatidosis; Mucosulfatidosis; Sulfatidosis juvenile, Austin type

Definition

Multiple sulfatase deficiency is a lysosomal storage disorder that mainly affects the brain, skin, and skeleton.

Types

Because the signs and symptoms of multiple sulfatase deficiency vary widely, researchers have split the condition into three types: neonatal, late-infantile, and juvenile.

Epidemiology

Multiple sulfatase deficiency is estimated to occur in 1 per million individuals worldwide. More than 140 cases have been reported in the scientific literature.

Cause

• Multiple sulfatase deficiency is caused by mutations in the SUMF1 gene. This gene provides instructions for making an enzyme called formylglycine-generating enzyme (FGE). This enzyme is found in a cell structure called the endoplasmic reticulum, which is involved in protein processing and transport.
• The FGE enzyme modifies other enzymes called sulfatases, which aid in breaking down substances that contain chemical groups known as sulfates. These substances include a variety of sugars, fats, and hormones.
• Most SUMF1 gene mutations severely reduce the function of the FGE enzyme or lead to the production of an unstable enzyme that is quickly broken down. The activity of multiple sulfatases is impaired because the FGE enzyme modifies all known sulfatase enzymes. Sulfate-containing molecules that are not broken down build up in cells, often resulting in cell death. The death of cells in particular tissues, specifically the brain, skeleton, and skin, cause many of the signs and symptoms of multiple sulfatase deficiency.
• Research indicates that mutations that lead to reduced FGE enzyme function are associated with the less severe cases of the condition, whereas mutations that lead to the production of an unstable FGE enzyme tend to be associated with the more severe cases of multiple sulfatase deficiency.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

The neonatal type is the most severe form, with signs and symptoms appearing soon after birth. Affected individuals have deterioration of tissue in the nervous system (leukodystrophy), which can contribute to movement problems, seizures, developmental delay, and slow growth.

• They also have dry, scaly skin (ichthyosis) and excess hair growth (hypertrichosis).
• Skeletal abnormalities can include abnormal side-to-side curvature of the spine (scoliosis), joint stiffness, and dysostosis multiplex, which refers to a specific pattern of skeletal abnormalities seen on x-ray. Individuals with the neonatal type typically have facial features that can be described as "coarse."
• Affected individuals may also have hearing loss, heart malformations, and an enlarged liver and spleen (hepatosplenomegaly). Many of the signs and symptoms of neonatal multiple sulfatase deficiency worsen over time.

The late-infantile type is the most common form of multiple sulfatase deficiency.

• It is characterized by normal cognitive development in early childhood followed by a progressive loss of mental abilities and movement (psychomotor regression) due to leukodystrophy or other brain abnormalities.
• Individuals with this form of the condition do not have as many features as those with the neonatal type, but they often have ichthyosis, skeletal abnormalities, and coarse facial features.

The juvenile type is the rarest form of multiple sulfatase deficiency.

• Signs and symptoms of the juvenile type appear in mid- to late childhood. Affected individuals have normal early cognitive development but then experience psychomotor regression; however, the regression in the juvenile type usually occurs at a slower rate than in the late-infantile type.
• Ichthyosis is also common in the juvenile type of multiple sulfatase deficiency.
• Life expectancy is shortened in individuals with all types of multiple sulfatase deficiency. Typically, affected individuals survive only a few years after the signs and symptoms of the condition appear, but life expectancy varies depending on the severity of the condition and how quickly the neurological problems worsen.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Abnormality of peripheral nerve conduction
• Developmental regression(Loss of developmental milestones)
• Global developmental delay
• Hepatomegaly(Enlarged liver)
• Ichthyosis
• Intellectual disability(Mental deficiency)
• Mucopolysacchariduria
• Neonatal hypotonia(Low muscle tone, in neonatal onset)
• Rapid neurologic deterioration
• Splenomegaly(Increased spleen size)
• Visual impairment(Impaired vision)

30%-79% of people have these symptoms

• Abnormality of retinal pigmentation
• Anteverted nares(Nasal tip, upturned)
• Broad hallux phalanx(Broad bone of big toe)
• Broad thumb(Broad thumbs)
• Cataract(Clouding of the lens of the eye)
• Coarse facial features(Coarse facial appearance)
• Coarse hair(Coarse hair texture)
• Corneal opacity
• Depressed nasal bridge(Depressed bridge of nose)
• Hydrocephalus(Too much cerebrospinal fluid in the brain)
• Joint stiffness(Stiff joint)
• Macrocephaly(Increased size of skull)
• Optic atrophy
• Seizure
• Sensorineural hearing impairment
• Short stature(Decreased body height)
• Smooth philtrum
• Thick eyebrow(Bushy eyebrows)

5%-29% of people have these symptoms

• Microcephaly(Abnormally small skull

Diagnosis

The diagnosis of multiple sulfatase deficiency is established in a proband with low activity levels in at least two sulfatase enzymes and/or biallelic pathogenic variants in SUMF1 identified by molecular genetic testing.

Multiple sulfatase deficiency should be suspected in individuals with the following clinical, laboratory, and imaging findings.

Clinical findings

• Developmental delay with subsequent neurologic regression and psychomotor retardation
• Macrocephaly with or without hydrocephalus
• Epilepsy
• Poor growth with a progressive decrease in growth rate
• Coarse facial features
• Recurrent otitis media and/or upper respiratory tract infections
• Progressive hearing loss
• Hepatosplenomegaly
• Skeletal changes including kyphosis, gibbus deformity, hip dislocation, genu valgum
• Cardiac hypertrophy or thickening of cardiac valves
• Ichthyosis

Laboratory findings

• Decreased activity of at least two sulfatase enzymes on lysosomal enzyme testing analysis
• Elevated urinary glycosaminoglycan levels
• Elevated urinary sulfatides

Imaging findings

• Abnormal brain MRI showing progressive demyelination, prominence of the perivascular spaces, cerebral volume loss, and/or hydrocephalus
• Skeletal radiographs demonstrating features of dysostosis multiplex including anomalies of the vertebrae, hands, feet, long bones, and skull

Treatment

• Progressive hydrocephalus, seizures, spasticity, spine instability or stenosis, eye anomalies, cardiovascular disease, hearing loss, poor growth, dental anomalies, developmental delays, and respiratory issues are managed in the standard fashion.
• Obstructive sleep apnea may be treated with adenoidectomy and/or tonsillectomy, although affected individuals have a higher surgical complication rate; ventilator support (CPAP, BiPAP) can also be considered.
• Precautions are needed during anesthesia to address airway maintenance, as progressive upper airway obstruction and cervical spine instability are common.
• Poor bone health may require supplementation with vitamin D and encouragement of weight-bearing exercises. Alternative routes for nutrition (tube feeding) are frequently necessary.[1].

NIH genetic and rare disease info

• NIH info on Multiple sulfatase deficiency

Multiple sulfatase deficiency is a rare disease.

Multiple sulfatase deficiency Resources
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