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Lysosomal Storage Disorders Presenting in the Neonate


Key Points

  • Lysosomal storage diseases are a genetically and phenotypically heterogeneous group of metabolic disorders caused by multisystemic accumulation of complex substrates.

  • Clinical manifestations of lysosomal storage diseases in the neonatal period are myriad, including nonimmune hydrops fetalis, respiratory distress, sepsis, macular cherry-red spot, dysmorphic facial features, dysostosis multiplex, and hepatosplenomegaly.

  • Newborn screening for certain lysosomal storage diseases such as mucopolysaccharidosis type I and Pompe disease is included on the Recommended Uniform Screening Panel and has been implemented in most states.

  • Growing recognition of neonatal symptoms and improved analytic methods has led to early diagnosis and treatment of lysosomal storage diseases in the newborn period.

  • Treatment options for lysosomal storage diseases are advancing rapidly, including enzyme replacement therapy, substrate reduction therapy, and hematopoietic stem cell transplantation. Gene therapy trials are ongoing.

Introduction

Lysosomes are single membrane–bound intracellular organelles that contain enzymes called hydrolases. These lysosomal enzymes are responsible for splitting large molecules into simple, low-molecular-weight compounds, which can be recycled. The endogenous materials digested by lysosomes are derived from endocytosis and phagocytosis, and separated from other intracellular materials and delivered to lysosomes through the process of autophagy.

Lysosomal storage diseases (LSDs) are a genetically and phenotypically diverse group of metabolic disorders caused by enzyme deficiencies that result in the pathologic accumulation of complex substrates within lysosomes throughout various tissues in the body. LSDs are classified according to the stored compound. The common element of all compounds digested by lysosomal enzymes is a carbohydrate portion attached to a protein or lipid. These glycoconjugates include glycolipids, glycoproteins, and glycosaminoglycans (GAGs).

Glycolipids are large molecules with carbohydrates attached to a lipid moiety. Sphingolipids, globosides, gangliosides, cerebrosides, and lipid sulfates all are glycolipids. The different classes of glycolipids are distinguished from one another primarily by different polar groups at C-1. Sphingolipids are complex membrane lipids composed of one molecule of each of the amino alcohol sphingosine, a long-chain fatty acid, and various polar head groups attached by a β-glycosidic linkage. Sphingolipids occur in the blood and nearly all tissues of the body, the highest concentration being found in white matter of the central nervous system (CNS). In addition, various sphingolipids are components of the plasma membrane of practically all cells. The core structure of natural sphingolipids is ceramide, a long-chain fatty acid amide derivative of sphingosine. Free ceramide, an intermediate in the biosynthesis and catabolism of glycosphingolipids and sphingomyelin, composes 16% to 20% of normal lipid content of stratum corneum of the skin. Sphingomyelin, a ceramide phosphocholine, is one of the principal structural lipids of membranes of nervous tissue.

Cerebrosides are a group of ceramide monohexosides with a single sugar, either glucose or galactose, and an additional sulfate group on galactose. The two most common cerebrosides are galactocerebroside and glucocerebroside. The largest concentration of galactocerebroside is found in the brain. Glucocerebroside is an intermediate in the synthesis and degradation of more complex glycosphingolipids. Gangliosides, the most complex class of glycolipids, contain several sugar units and one or more sialic acid residues. Gangliosides are normal components of cell membranes and are found in high concentrations in ganglion cells of the CNS, particularly in nerve endings and dendrites. GM1 is the major ganglioside in the brain of vertebrates.

GAGs, also called mucopolysaccharides, are complex heterosaccharides consisting of long sugar chains rich in sulfate groups. The polymeric chains are bound to specific proteins (core proteins). Glycoproteins contain oligosaccharide chains (long sugar molecules) attached covalently to a peptide core. Glycosylation occurs in the endoplasmic reticulum and Golgi apparatus. Most glycoproteins are secreted from cells and include transport proteins, glycoprotein hormones, complement factors, enzymes, and enzyme inhibitors. There is extensive diversity in the composition and structure of oligosaccharides.

The degradation of glycolipids, GAGs, and glycoproteins occurs within lysosomes of phagocytic cells, related to histiocytes and macrophages, in any tissue or organ. A series of hydrolytic enzymes cleaves specific bonds, resulting in stepwise removal of constituents such as sugars and sulfate as well as degrading complex glycoconjugates to their basic building blocks. LSDs most commonly result when an inherited defect causes significantly decreased activity in one of these hydrolases.

Our understanding of the pathogenesis of LSDs continues to evolve. In addition to catabolic enzyme deficiencies, abnormal autophagy, aberrant vesicular trafficking, cellular signaling, and homeostasis have also been implicated in the multifaceted pathomechanism of LSDs. Regardless of etiology, incompletely metabolized molecules accumulate, especially within the tissue responsible for catabolism of the glycoconjugate. Excess storage material may be excreted in urine.

While individually rare, there are over 70 different LSDs, with a collective incidence of approximately 1 in 5000 live births. Approximately 20 of these LSDs may present in the newborn period, of which 14 are reviewed in this chapter.

The neonatal clinical presentation of LSDs includes nonimmune hydrops fetalis, respiratory distress, seizures, cherry-red spot in the macula, dysmorphic facial features, sepsis, dysostosis multiplex, and/or hepatosplenomegaly. However, symptoms may be nonspecific and physical findings such as skeletal abnormalities may not be apparent in the neonatal period. Diagnosis is typically confirmed with enzyme assay in conjunction with molecular testing.

Clinical Presentations

Table 30.1 summarizes the clinical characteristics of the neonatal presentations of LSDs.

Table 30.1
Lysosomal Storage Disorders in the Newborn Period: Genetic and Clinical Characteristics of Neonatal Presentation
Disorder Onset Facies Neurologic Findings Distinctive Features Eye Findings Cardiovascular Findings Dysostosis Multiplex Hepatomegaly/Splenomegaly Defect Gene Location/Molecular Findings Ethnic Predilection
Acid sphingomyelinase deficiency (Niemann–Pick disease type A) Early infancy Frontal bossing Difficulty feeding, apathy, deafness, blindness, hypotonia Brownish-yellow skin, xanthomas Cherry-red spot (50%) — — ++/+ Sphingomyelinase deficiency SMPD1 gene at 11p15.4; three of 18 mutations account for approximately 92% of mutant alleles in the Ashkenazi population 1:40,000 in Ashkenazi Jews with carrier frequency of 1:60
Niemann–Pick C disease Birth–3 months Normal Developmental delay, vertical gaze paralysis, hypotonia, later spasticity — — — — +/++ Abnormal cholesterol esterification NPC1 gene at 18q11 accounts for >95% of cases; HE1 gene mutations may account for remaining cases Increased in French Canadians of Nova Scotia and Spanish Americans in the southwest United States
Gaucher disease type 2 In utero–6 months Normal Poor suck and swallow, weak cry, squint, trismus, strabismus, opsoclonus, hypertonic, later flaccidity Congenital ichthyosis, collodion skin — — — +/++ Glucocerebrosidase deficiency 1q21; large number of mutations known; five mutations account for approximately 97% of mutant alleles in the Ashkenazi population but approximately 75% in the non-Jewish population Panethnic
Krabbe disease 3–6 months Normal Irritability, tonic spasms with light or noise stimulation, seizures, hypertonia, later flaccidity Increased CSF protein level Optic atrophy — — –/– Galactocerebrosidase deficiency 14q 24.3–q32.1; >60 mutations with some common mutations in specific populations Increased in Scandinavian countries and in a large Druze kindred in Israel
GM1 gangliosidosis Birth Coarse Poor suck, weak cry, lethargy, exaggerated startle, blindness, hypotonia, later spasticity Gingival hypertrophy, edema, rashes Cherry-red spot (50%) — + +/+ β-Galactosidase deficiency 3pter–3p21; heterogeneous mutations; common mutations in specific populations Panethnic
Mucopolysaccharidosis type I Childhood Variable coarseness Mild to severe mental retardation Gibbus deformity Variable corneal clouding Variable ++ Variable α-L-iduronidase deficiency IDUA gene at 4p16.3; heterogeneous mutations Panethnic
Mucopolysaccharidosis type VII In utero–childhood Variable coarseness Mild to severe mental retardation Nonimmune fetal hydrops Variable corneal clouding Variable ++ Variable β-Glucuronidase deficiency GUSB gene at 7q21.2–q22; heterogeneous mutations Panethnic
Wolman disease First weeks of life Normal Mental deterioration Vomiting, diarrhea, steatorrhea, abdominal distention, failure to thrive, anemia, adrenal calcifications — — — +/+ Lysosomal acid lipase deficiency 10q23.2–q23.3; variety of mutations identified Increased in Iranian Jews and in non-Jewish and Arab populations of Galilee
Farber disease Birth- infancy Normal Joint swelling with nodules, hoarseness Normal macula, corneal opacities — — ++/++ Acid ceramidase deficiency ASAH1 gene at 8p21.3–p22 Panethnic
Congenital sialidosis In utero–birth Coarse, edema Mental retardation, hypotonia Neonatal ascites, inguinal hernias, renal disease Corneal clouding — + +/+ Neuraminidase (sialidase) deficiency NEU1 gene at 6p21 Panethnic
Galactosialidosis In utero–birth Coarse Mental retardation, occasional deafness, hypotonia Ascites, edema, inguinal hernias, renal disease, telangiectasias Cherry-red spot, corneal clouding Cardiomegaly progressing to failure + +/+ Absence of a protective protein that safeguards neuraminidase and β-galactosidase from premature degradation CTSA gene at 20q13.12 Panethnic
Infantile sialic acid storage disease In utero–birth Coarse, dysmorphic Mental retardation, hypotonia Ascites, anemia, diarrhea, failure to thrive — Congestive heart failure + +/+ Defective transport of sialic acid out of the lysosome SLC17A5 gene at 6q13 Panethnic
I-cell disease In utero–birth Coarse Mental retardation, deafness Gingival hyperplasia, restricted joint mobility, hernias Corneal clouding Valvular disease, congestive heart failure, cor pulmonale ++ +++/+++ Lysosomal enzymes lack mannose 6-phosphate recognition marker and fail to enter the lysosome (phosphotransferase deficiency, 3-subunit complex [α2 β2 γ2]) Enzyme encoded by two genes; α and β subunits encoded by GNPTAB gene at 12p23.2; γ subunit encoded by GNPTAG gene at 16p13.3 Panethnic
Mucolipidosis type IV Birth–3 months Normal Mental retardation, hypotonia — Severe corneal clouding, retinal degeneration, blindness — — —/— Unknown; some patients with partial deficiency of ganglioside sialidase MCOLN1 gene at 19p13.2–13.3 encoding mucolipin 1; two founder mutations accounting for 95% of mutant alleles in the Ashkenazi population Increased in Ashkenazi Jews
—, Not seen; +, typically present, usually not severe; ++, usually present and moderately severe; +++, always present, usually severe; CSF , cerebrospinal fluid; HSM , hepatosplenomegaly.

Acid Sphingomyelinase Deficiency (Niemann–Pick Disease Types A and B)

Etiology

Acid sphingomyelinase deficiency (ASMD; also known as Niemann-Pick disease types A and B [NPD-A and NPD-B]) is caused by deficiency of the enzyme sphingomyelinase. Historically, ASMD was grouped with Niemann-Pick disease type C (NPC) due to similar pathology findings of accumulated foamy sea-blue histiocytes, but they are now understood to be genetically distinct disorders. Sphingomyelinase normally catalyzes the breakdown of sphingomyelin to form ceramide and phosphocholine. Sphingomyelinase deficiency results in the pathologic accumulation of sphingomyelin within lysosomes particularly in the nervous system, spleen, liver, and lungs. Cholesterol is also stored, suggesting that its metabolism is tied to that of sphingomyelin. Sphingomyelin normally composes 5% to 20% of phospholipids in the liver, spleen, and brain, but in ASMD it can compose up to 70% of phospholipids. Patients with severe ASMD usually have less than 5% of normal enzyme activity.

Clinical Features

ASMD was historically classified into NPD-A and NPD-B based on severity, clinical manifestations, and age of onset. NPD-A presents as severe, infantile-onset neurovisceral disease, whereas NPD-B presents later in childhood. Patients with NPD-A typically present with massive hepatosplenomegaly by 3 months of age. Other clinical features include constipation, feeding difficulties, and vomiting, with consequent failure to thrive, and respiratory failure. Patients eventually appear strikingly emaciated with a protuberant abdomen and thin extremities. Neurologic disease is evident by 6 months of age, with hypotonia, decrease or absence of deep tendon reflexes, and weakness. Loss of motor skills, spasticity, rigidity, irritability, and loss of vision and hearing occur later. Seizures are rare. A macular cherry-red spot is present in about half of cases, and the electroretinographic findings are abnormal. Respiratory infections are common. The skin may have an ochre or brownish-yellow color, and xanthomas have been observed. Radiographic findings consist of widening of medullary cavities, cortical thinning of long bones, and osteoporosis. In the brain and spinal cord, neuronal accumulation of sphingomyelin is widespread, leading to cytoplasmic swelling together with atrophy of cerebellum. Bone marrow and tissue biopsy samples may show foam cells or sea-blue histiocytes, which represent lipid-laden cells of the monocyte–macrophage system. Similarly, vacuolated lymphocytes or monocytes may be present in peripheral blood. Tissue cholesterol levels may be threefold to tenfold that of normal, and patients may have a microcytic anemia and thrombocytopenia. Death occurs by 2 to 3 years of age after a rapid neurodegenerative course.

Niemann-Pick Disease Type C

Etiology

NPC is caused by a defect in the intracellular transport of exogenous low-density lipoprotein (LDL)-derived cholesterol, which leads to impaired esterification of cholesterol and trapping of unesterified cholesterol in lysosomes. The incidence is roughly 1 in 100,000 births. NPC is caused by a defect of either the NPC1 or NPC2 protein. The latter binds cholesterol liberated by acid lipase and shuttles it to NPC1, which facilitates egress of cholesterol from late endosomes/lysosomes to the endoplasmic reticulum. There is secondary storage of sphingomyelin. Sphingomyelinase activity appears normal or elevated in most tissues but is partially deficient in fibroblasts from most patients with this disorder. Storage of sphingomyelin in tissues is much less than in ASMD and is accompanied by additional storage of unesterified cholesterol, phospholipids, and glycolipids in the liver and spleen. Only glycolipids levels are increased in the brain.

Clinical Features

The age of onset, clinical features, and natural history of NPC are highly variable. Onset can occur from birth to adulthood. Findings on prenatal ultrasound include fetal ascites or hydrops, hepatosplenomegaly, intrauterine growth restriction, and oligohydramnios or polyhydramnios. In the neonatal period, 50% of infants have conjugated hyperbilirubinemia, which usually resolves spontaneously. Liver failure, sometimes misdiagnosed as fetal hepatitis, and respiratory failure can occur, with neurologic symptoms appearing later in childhood in those who survive. In the severe infantile form, hepatosplenomegaly is common and often present at birth, accompanied by hypotonia and delayed motor development. Further neurologic regression is usually evident by the age of 1 to 1.5 years, in association with vertical supranuclear ophthalmoplegia, progressive ataxia, dystonia, spasticity, drooling, dysphagia, and dysarthria. Seizures are rare. Foam cells and sea-blue histiocytes may be found in many tissues. Neuronal accumulation of glycolipids with cytoplasmic ballooning, inclusions, meganeurites, and axonal spheroids is also seen. The average survival is 5 years or less. Patients with mutations in the NPC2 gene have pronounced pulmonary involvement as accumulation of cholesterol in alveolar macrophages leads to abnormal surfactant composition, resulting in early death due to respiratory failure.

Gaucher Disease Type 2 (Acute Neuronopathic)

Etiology

Gaucher disease is caused by deficiency of lysosomal glucocerebrosidase and results in storage of glucocerebroside in mononuclear phagocytes. Glucocerebrosidase splits glucose from cerebroside, yielding ceramide and glucose. Three types of Gaucher disease have been defined. Type 1, the non-neuronopathic form, is the most common and is distinguished from types 2 and 3 by the lack of CNS involvement. Type 1 disease most commonly manifests itself in early childhood but may do so in adulthood. Type 2 disease, the acute neuronopathic form, is the rarest form and is characterized by infantile onset of severe CNS involvement. Type 3 disease, the subacute neuronopathic form, presents in childhood with slower neurologic progression. Although there is significant variability in clinical presentation among individuals with the same mutations in GBA , there are some correlations between certain mutations and clinical symptoms involving the CNS. A few patients with Gaucher disease type 2 have a deficiency of saposin C, a cohydrolase required by glucocerebrosidase.

Clinical Features

The age of onset of Gaucher disease type 2 is approximately 3 months. Clinical features include early hepatosplenomegaly (splenomegaly predominates) with later neurologic deterioration including bulbar signs, hyperextension of the neck, spasticity, and horizontal gaze palsy. Hydrops fetalis, congenital ichthyosis, and collodion skin are well-described presentations. In a review of 18 cases of Gaucher disease manifesting in the newborn period, Sidransky et al. found that eight patients had associated dermatologic findings, and six patients had hydrops. The cause of the association of such findings in Gaucher disease is unclear, although the enzyme deficiency appears to be directly responsible. Ceramides have been shown to be major components of intracellular bilayers in epidermal stratum corneum, and they have an important role in skin homeostasis. Therefore Gaucher disease should be considered in the differential diagnosis for infants with hydrops fetalis and congenital ichthyosis. For the subset of patients who present in the prenatal period or at birth, death commonly occurs within 2 to 3 months. In other infants, splenomegaly, cachexia, and chronic pulmonary disease are progressive, and death follows within 2 years.

Krabbe Disease (Globoid Cell Leukodystrophy)

Etiology

The synonym for Krabbe disease, globoid cell leukodystrophy, is derived from the finding of large numbers of multinuclear macrophages in cerebral white matter that contain undigested galactocerebroside. Krabbe disease is caused by a deficiency of lysosomal galactocerebroside β-galactosidase, which degrades galactocerebroside to ceramide and galactose, resulting in storage of galactocerebroside. Galactocerebroside is present almost exclusively in myelin sheaths. Accumulation of the toxic metabolite psychosine, another substrate for the enzyme, leads to early destruction of oligodendroglia. Impaired catabolism of galactosylceramide is also important in the pathogenesis of the disease. Saposin A is an activator protein that aids the galactocerebroside β-galactosidase enzyme. Saposin A deficiency presents with a Krabbe-like phenotype.

Clinical Features

The age of onset ranges from the first weeks of life to adulthood. The typical age of onset of infantile Krabbe disease is between 3 and 6 months, but there are cases in which neurologic symptoms are evident within weeks after birth. Signs and symptoms are confined to the nervous system; no visceral involvement is present. The clinical course has been divided into three stages. In stage I, patients who appeared relatively normal after birth begin to exhibit hyperirritability, vomiting, episodic fevers, hyperesthesia, tonic spasms with light or noise stimulation, stiffness, and seizures. Peripheral neuropathy is present, but reflexes are increased. Stage II is marked by CNS deterioration and hypertonia that progresses to hypotonia and flaccidity. Deep tendon reflexes are eventually lost. Patients with stage III disease are decerebrate, deaf, and blind with hyperpyrexia, hypersalivation, and frequent seizures. Routine laboratory findings are unremarkable except for an elevation of the level of cerebrospinal fluid protein. Cerebral atrophy and demyelination become evident in the CNS, and segmental demyelination, axonal degeneration, fibrosis, and macrophage infiltration are common in the peripheral nervous system. The segmental demyelination of peripheral nerves is demonstrated by the finding of decreased motor nerve conduction. The white matter is severely depleted of all lipids, especially glycolipids, and nerve and brain biopsies show globoid cells. Death from hyperpyrexia, respiratory complications, or aspiration occurs at a median age of 13 months.

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