Overview
Neurodegenerative diseases are characterized by the progressive loss of previously acquired developmental milestones due to the destruction of gray matter and/or white matter structures. They can present in children as recurrent vomiting, feeding difficulties, failure to thrive, sepsis, intrauterine growth retardation, developmental delay, intellectual disability, and seizures.
This summary will focus on neurometabolic diseases, specifically lysosomal storage diseases (lipidoses, mucopolysaccharidoses, and some types of glycogen storage disease).
While rare, such disorders must be distinguished on clinical evaluation from neurodegenerative conditions resulting from infection, trauma, and space-occupying lesions. Early, accurate diagnosis alllows for the provision of prognostic information to parents and, in some cases, early implementation of available therapies to prevent permanent organ damage.
Introduction
Lipidoses, mucopolysaccharidoses, and type II glycogen storage disease are classified as lysosomal storage diseases due to the abnormal accumulation of breakdown products (lipids, mucopolysaccharides, and glycogen, respectively) in the lysosome. The lysosome is a waste disposal organelle in the cell, and the aforementioned diseases result from deficiency of one or more lysosomal enzymes used for recycling cellular substrates.
The combined incidence of lysosomal storage disorders is 1 in 1500 to 7000 live births. The majority are inherited in an autosomal recessive pattern, with a few exceptions which are inherited in a X-linked recessive pattern (Fabry disease, Hunter syndrome, Danon disease). Ethnicity is an important consideration as certain ethnic groups have an increased carrier frequency for various lysosomal storage disorders. Notable examples include Tay-Sachs disease and Gaucher disease in those of Ashkenazi Jewish ancestry, galactosialidosis in those of Japanese ancestry and Pompe disease in those of African or Chinese ancestry.
Clinical Features
Children with lysosomal storage diseases often appear normal at birth and become symptomatic over the first few months or even years of life. In general, the less severe the disease, the later it will present.
Symptoms vary based on the specific disorder, but newborns may present with the following:
1. Neurologic: Hypotonia, weakness, seizures, developmental delay, irritability, strabismus
2. Respiratory: Recurrent respiratory infections, hoarseness, impaired cough, respiratory distress
3. Endocrine: Osteopenia, congenital adrenal hyperplasia
4. Cardiovascular: Cardiomegaly, congenital heart failure, arrhythmias, cardiomyopathy
5. Dysmorphic Features: Microcephaly, micrognathia, bilateral club feet, macroglossia, coarse facies, joint contractures, craniosynostosis
6. Gastrointestinal: Hepatosplenomegaly, cholestasis
7. Skin: Hypopigmentation, telangiectasias, congenital ichthyosis
8. Ocular: Corneal clouding, glaucoma, cherry-red spots, bilateral cataracts
9. Hematologic: Anemia, thrombocytopenia
10. Non-Immune Hydrops fetalis and congenital ascites
Children most commonly present with hepatosplenomegaly, coarse facial features, developmental delay, short stature and/or dysostosis multiplex (characteristic radiographic changes due to abnormal skeletal cartilage development).
Differential Diagnosis
There are more than 70 known lysosomal storage disorders, including the following:
1. Gaucher’s disease (lipidosis)
a. Most common lysosomal storage disorder
b. Autosomal recessive inheritance
c. Deficient enzyme: Glucocerebrosidase
d. Accumulated substrate: Glucocerebroside
e. Classic "gaucher cells" (crinkles paper appearance) can be seen in bone marrow biopsy
f. Clinical features: Hepatosplenomegaly, cognitive and psychomotor regression (absent in type 1), bone crises, and necrosis of femur
2. Tay-Sachs disease (lipidosis)
a. Autosomal recessive inheritance
b. Deficient enzyme: Hexosaminidase A
c. Accumulated substrate: GM2 ganglioside
d. Clinical features: Onset in early infancy, developmental delay, cherry-red spot on macula, hyperacusis, myoclonic seizures
Learn more about Tay-Sachs here
3. Niemann-Pick disease (lipidosis)
a. Autosomal recessive inheritance
b. Deficient enzyme: Sphingomyelinase
c. Accumulated substrate: Sphingomyelin
d. Clinical features: Hypotonia/areflexia, hepatosplenomegaly, cherry-red spot on macula, cognitive regression
4. Hurler’s syndrome (mucopolysaccharidosis)
a. Autosomal recessive inheritance
b. Deficient enzyme: Alpha-L-iduronidase
c. Accumulated substrate: Heparan sulfate, dermatan sulfate
d. Clinical features: Developmental delay, course facies, corneal clouding, hepatosplenomegaly, dysostosis multiplex
5. Pompe’s disease (type II glycogen storage disease)
a. Autosomal recessive inheritance
b. Deficient enzyme: Alpha-1,4-glucosidase
c. Accumulated substrate: Glycogen
d. Clinical features: Cardiomegaly, liver disease, hypotonia, muscle wasting, weakness, short P-R interval
Other lysosomal storage disorders include Krabbe’s disease (AR lipidosis), metachromatic leukodystrophy (AR lipidosis), and Fabry’s disease (X-linked lipidosis).
Clinical evaluation and Treatment
Due to the overlap of many clinical features across subtypes of lysosomal storage diseases, diagnosis by clinical presentation is challenging. Definitive diagnosis can be achieved by laboratory assays for:
1. Storage products: easiest screening test; checks urine for presence of glycosaminoglycans and oligosaccharides
2. Enzymatic activity: Slightly more invasive testing, fluorometric assay of enzymatic activity in leukocytes or cultured skin fibroblasts
3. DNA mutations: Not available for all diseases, however when available it can help guide pre-natal counseling, treatment and prognostication
Population screening is not routinely performed except for among high-risk ethnic groups, such as the Ashkenazi Jewish population. Testing may also be performed in families with a known history of lysosomal storage diseases.
Lysosomal storage disorders are not currently included in newborn screening tests in the United States, however LSD advocacy groups are increasingly demanding newborn screening and pilot newborn screening programs for Fabry, Gaucher, Niemann-Pick and Pompe have been initiated in some states. There is on-going discussion over the ethical implications of expanding newborn screening to include these diseases.
Treatment and Prognosis
Therapies for most lysosomal storage diseases are limited. In the past, treatment has focused on supportive care and symptomatic management. Targets include correction of metabolic abnormalities like lactic acidosis, the removal of toxic storage products, and the treatment of cardiac irregularities and other life-threatening conditions.
Over the last 20 years, direct IV delivery of the deficient enzyme or enzyme replacement therapy (ERT) has become available for Fabry disease, Gaucher disease, mucopolysaccharidoses I, II & VI, and Pompe disease. Clinical trials for Niemann-Pick disease, alpha-mannosidosis, mucopolysaccharidosis IV and lysosomal acid lipase deficiency are on-going. While sucessful at reducing the disease burden in bone and viscera, the sucess of ERT has been limited by its lack of effect on CNS manifestations (ERT cannot cross the blood-brain barrier). Other challenges include immunologic response of patients with no residual enyzme activity, the need for life-long therapy and the high cost (up to $250,000 per patient yearly).
Oral sustrate reduction therapy (SRT), which inhibits glycosphingolipid synthesis thus slowing accumulation of breakdown products, has been developed for Gaucher disease. It is primarily used when ERT is refused, however it is also being studied as a part of combination therapy with ERT.
Hemapoietic stem cell transplantation (bone marrow transplantation) has been attempted to replace defective enzymes in many types of LSD with varying results. It has been most sucessful in the treatment of Hurler syndrome patients when attempted prior to the age of 2. Nonallogenic cord blood transplantation has shown some effectiveness in Hurler syndome and Krabbe disease when a matched bone marrow donor is not available.
Active areas of research include gene therapy (delivery of the wild-type gene for the deficient enzyme directly to a cell via viral vector), pharmacologic chaperone therapy (small compounds which "rescue" mutant enzymes) and intrathecal administration of ERT.