Congenital Disorders of Glycosylation, Peroxisomal Disorders, and Smith-Lemli-Opitz Syndrome

Key Points

The phenotypic spectrum of glycosylation disorders is broad and ranges from mild to severe and from single-organ system to multisystem disease; glycosylation defects should be considered in any unexplained clinical condition, but especially in multiorgan disease with neurologic involvement.
Diagnosis of congenital disorders of glycosylation mainly relies on next-generation sequencing techniques. Treatment is largely supportive except for rare exceptions where nutritional supplements are effective.
Peroxisomal disorders are a broad and heterogeneous group of inherited diseases with most often multisystem features, including craniofacial dysmorphism, neurologic dysfunction, including hearing and vision dysfunction, hepatodigestive dysfunction, renal cysts, and skeletal abnormalities seen in the newborn period.
Diagnosis of peroxisomal disorders is best made by next-generation sequencing techniques following abnormal biochemical screening test findings. Treatment is supportive.
Smith-Lemli-Opitz syndrome (SLOS) is a multisystemic, developmental, and dysmorphic disorder with a wide clinical spectrum caused by a defect in cholesterol biosynthesis.
Diagnosis of SLOS is based on elevated 7-dehydrocholesterol and 8-dehydrocholesterol levels in the blood and treatment is largely supportive.

Congenital Disorders of Glycosylation

Epidemiology of Congenital Disorders of Glycosylation

Congenital disorders of glycosylation (CDGs) are a group of more than 140 genetic diseases which involve various defects in the process of modifying proteins, lipids, or other biomolecules with glycans (sugar molecules or chains). Glycosylation, the addition of glycans to biomolecules, is essential to many biologic processes, such as aiding with correct folding, protecting against premature destruction, directing intracellular localization and transport, and modifying the biologic function of these biomolecules.

The first discovered CDG (PMM2-CDG) was described by Professor Jaak Jaeken in 1980 and was initially termed “carbohydrate-deficient glycoprotein syndrome” due to abnormalities seen in multiple serum glycoproteins in the affected individuals. When several more human glycosylation disorders were identified, this group of disorders was renamed “congenital disorders of glycosylation.” The decision was made to designate types of CDG into either a group I or II disorder based on the transferrin pattern obtained by isoelectro-focusing with specific diagnoses alphabetized consecutively as they were identified (i.e., CDG Ia, Ib, Ic, IIa, IIb, etc.). Improved molecular diagnostics expanded the definition of CDGs to include genetic diseases that primarily disrupt the process of formation of any glycoconjugate (i.e., glycoproteins, glycolipids, glycosaminoglycan [GAG], etc.), resulting in an exponential growth of the number of pathways and individual disorders. In 2009, the nomenclature was updated, and currently specific CDG types are named starting with the affected gene symbol (not in italics) followed by -CDG (e.g., CDG-Ia is now PMM2-CDG).

It is estimated that approximately 3% to 4% (~700) of our genes encode for proteins involved with the glycosylation process. The glycosylation process takes place in a variety of locations within the cell including the cytosol, endoplasmic reticulum (ER), and Golgi apparatus. The underlying mechanism for the clinical manifestations of most of CDGs is still unclear. Given the complexity of glycosylation, there are multiple methods to group these disorders. One classification schema groups CDGs into protein N-linked glycosylation defects, protein O-linked glycosylation defects, glycosylphosphatidylinositol (GPI) anchor glycosylation defects, lipid glycosylation defects, and defects in multiple glycosylation and other pathways. In this chapter, we use this classification method to help organize our discussion of CDGs that manifest in the neonatal period.

Clinical Presentation of Congenital Disorders of Glycosylation

Because so many biologic functions are dependent on the correct glycosylation, the phenotypic spectrum of CDG defects is extremely broad and ranges from mild to severe disease and from a single-organ system to multisystem disease. Clinical features alone are insufficient to define the CDG type. A CDG should be considered in any unexplained clinical condition, but especially in multiorgan disease with neurologic involvement ( Table 31.1 ).

Table 31.1

Common Clinical Features of Congenital Disorders of Glycosylation by Pathway

		KEY FEATURES BY SYSTEM
Pathway	Example Disorders	Neurologic	Ophthalmologic	Cardiologic	Gastroenterological	Hematologic	Renal	Endocrine	Dermatologic	Musculoskeletal/Other	Diagnostic Screen
N-linked glycosylation	PMM2-CDG, MPI-CDG, ALGx-CDG, MOGS-CDG	ID (except MPI), DD, seizures (50%), hypotonia, ataxia, dysmetria, dysarthria, peripheral neuropathy, cerebral and cerebellar atrophy, myasthenic syndrome	Strabismus, nystagmus, optic hypoplasia, retinal pigmentary changes, alacrima, congenital cataracts	Pericardial effusion, cardiomyopathy, fetal hydrops	Protein-losing enteropathy, diarrhea, failure to thrive, gastro-esophageal reflux, hepatopathy with elevated AST & ALT, edema and hypoalbuminemia, low cholesterol	Factors II, V, VII, VIII, IX, X, XI, Antithrombin III, Protein C, Protein S deficiency, increased bleeding tendency, thrombotic events, hypogammopathy, coagulopathy and thrombosis	Hyperechoic kidneys, microcystic changes, proteinuria	Abnormal thyroid function test, short stature, IGF1 deficiency, hypogonadotropic hypogonadism, hyperinsulemic hypoglycemia	Lipodystrophy, hypohidrosis	Osteopenia, kypho-scoliosis, dysmorphic features, skeletal dysplasia	Transferrin profiling, N-glycan profiling, urine oligosaccharide analysis (MOGS-CDG only)
O-linked glycosylation	GALNT3-CDG, B3GLCT-CDG, POMK-CDG, EXT1-CDG, CHST-CDG	ID (not universal), DD, congenital and later onset muscular dystrophy, hypotonia, polymicrogyria lissencephaly	Peters-plus syndrome, other structural eye abnormalities, glaucoma, isolated macular corneal dystrophy, corneal opacity, cataracts		Failure to thrive			Tumoral calcinosis with phosphatemia	Loose skin, Dowling Degos disease	Skeletal dysplasia, short stature, Ehlers-Danlos syndrome, hypermobility, exostoses, elevated creatine kinase, dysmorphic facies
Mixed glycosylation	COGx-CDG, TMEMx-CDG,	Seizures, ID (not universal), DD, microcephaly, hypotonia, cortical and cerebellar atrophy	All findings seen in N-linked pathway possible	Cardiomyopathy, congenital structural heart defects	All findings seen in N-linked pathway possible, isolated polycystic liver disease, high cholesterol, cholestatic liver disease, prenatal growth retardation	Isolated leukocyte adhesion deficiency, isolated congenital dyserythropoietic anemia type II, immunodeficiency	Obstructive uropathy, micropenis, hypospadias		Ichthyosis, cutis laxa, hypohidrosis, hyperkeratosis	Skeletal dysplasia, dysmorphic features, elevated creatine kinase	Transferrin profiling, N-glycan profiling, O-glycan profiling, APO-CIII profiling
GPI Anchor disorder	PIGx-CDG, PGAPx-CDG	Seizures, ID, DD, macrocephaly, hypotonia		Congenital heart defects, cardiomyopathy				Accelerated linear growth, advanced bone age, +/− hyperphosphatasia, hypophosphatasia		Dysmorphic features, multiple congenital anomalies	Flow cytometry studies using cell surface markers like FLAER and CD59 on granulocytes, lymphocytes, etc.
Lipid glycosylation	ST3GAL5-CDG (Amish Infantile Epilepsy syndrome)	Seizures, ID, DD, hypotonia, diffuse brain atrophy, irritability, microcephaly	Optic atrophy, cortical visual impairment		Failure to thrive				Dyspigmentation, “salt and pepper” pattern on skin macules

ALT , Alanine transaminase; AST , aspartate transaminase; DD , developmental disability; GPI , glycosylphosphatidylinositol; ID , intellectual disability; IGF1 , insulin-like growth factor 1.

N-Linked Protein Glycosylation Defects

Etiology

N-linked protein glycosylation, the process involved with attaching glycans to the asparagine residue of target proteins, was the first discovered and is the best understood glycosylation pathway in humans. Classically, these disorders were divided into two categories: type I which results in defects in N-glycan assembly, and type II which results from defects in N-glycan processing.

The initial assembly steps of N-glycosylation take place on the ER membrane, where sugars are attached in a stepwise manner to Dolichol-P to form a lipid-linked oligosaccharide (LLO). Sugars are donated by an activated nucleotide-sugar (UDP-GlcNAc and GDP-Man), with the attached nucleotide providing the necessary energy for the transfer of the sugar to the LLO. This oligosaccharide is then transferred to the nascent protein cotranslationally. Once the oligosaccharide chain has been transferred to the protein, further processing takes place. The oligosaccharide is then transported to the Golgi apparatus, where further processing occurs. Different types of CDGs have been found in affected individuals who have defective enzymes in individual steps of this complex pathway including the enzymes that form the dolichol backbone, transfer single sugars to the growing chain, interconvert activated monosaccharides, and transfer the oligosaccharide from dolichol to protein.

Clinical Features

N-linked glycosylation defects encompass many disorders. Taken together these several dozen disorders are typically multisystemic with significant neurologic involvement with the notable exception of MPI-CDG, in which development can be normal. The most common perinatal findings include hypotonia, nonspecific dysmorphic features (inverted nipples or abnormal fat pads occasionally present), feeding problems with growth delay, hepatopathy with elevated transaminases, and abnormal coagulation profiles. Discriminating findings include neonatal hemorrhages (including cerebral hemorrhage) and thrombotic events, pericardial effusion, strabismus, nystagmus, and other ophthalmologic findings, neonatal seizures, abnormal thyroid function screening results, and nonimmune hydrops. Transferrin glycosylation analysis previously performed using isoelectric-profiling and now performed using mass spectrometry methods show an abnormal glycosylation pattern in many, but not all, of these disorders.

Two disorders warrant special mention: PMM2-CDG (CDG-Ia) and MPI-CDG (CDG-Ib). PMM2-CDG (CDG-Ia) is the classic and most common presentation, and many other N-linked CDGs mirror its presentation. Most affected infants appear normal at birth, although a subset of individuals present with nonimmune hydrops with and without hypertrophic cardiomyopathy. In infancy, patients with PMM2-CDG can exhibit dysmorphic features, strabismus, nystagmus, hypoglycemia, and feeding difficulties; subsequently patients may exhibit growth failure, hypotonia, lipocutaneous abnormalities (including prominent fat pads on the buttocks), coagulopathy with thrombosis and bleeding, pericardial effusion, and mild to moderate hepatomegaly and hepatopathy. Approximately 20% of patients with PMM2-CDG die during the first year of life after a course of severe fluid imbalance and sometimes anasarca in response to infection or their underlying glycosylation disorder. Having survived infancy, patients with PMM2-CDG can live into their seventh and eighth decades. Later manifestations include intellectual disability, retinitis pigmentosa or retinal degeneration, renal cysts, coagulopathy, stroke-like episodes, thrombotic disease, cerebral and olivopontocerebellar hypoplasia, ataxia, dysarthria, peripheral neuropathy, followed by lower extremity atrophy, kyphoscoliosis, and hypogonadism.

MPI-CDG (CDG-Ib) stands out in this group of disorders because patients with MPI-CDG can have normal development and mannose is a known targeted therapy. Mortality rate during infancy is 23.5%, and the causes of death, when known, included hepatic failure and sepsis. The major manifestations of MPI-CDG are liver fibrosis, hepatomegaly, hypoglycemia, growth restriction, hypoalbuminemia, diarrhea, protein-losing enteropathy, edema, faltering growth, and coagulopathy. Mannose supplementation is not associated with improvement hepatopathy but improves most of the other manifestations. Thus, early diagnosis and treatment of MPI-CDG are imperative.

O-Linked Protein Glycosylation Defects

Etiology

O-glycosylation consists of attachment of a monosaccharide (mannose, fructose, or xylose), or the assembly of a glycan and its attachment to a serine or threonine residue of a target protein. O-glycosylation differs from N-glycosylation in that it does not take place at the same time as the protein is being translated, but occurs posttranslationally, exclusively in the Golgi apparatus, without further processing. O-glycosylation can be classified according to which type of sugar is attached to the serine or threonine. Examples of O-glycosylation include O-mannosylation, O-xylosylation, and O-fucosylation.

Clinical Features

Clinical features vary significantly depending on which type of O-glycosylation is defective. Deficiency of O-N-acetylgalatosamine linkage can lead to familial tumoral calcinosis with phosphatemia and massive calcium deposits in the skin and subcutaneous tissues. A defect in O-fucosylation has been shown to lead to Peters-plus syndrome characterized by anterior eye chamber defects, disproportionate short stature, developmental delay, and cleft lip and/or palate. O-fucosylation defects also lead to Dowling-Degos disease 2 characterized by abnormal skin pigmentation, and spondylocostal dysostosis type 3 characterized by short stature and vertebral abnormalities. Defects in O-xylosylation will lead to defective anchoring of GAGs to proteins and thus impaired proteoglycan formation. Defective O-xylosylation can lead to progeroid-type Ehlers-Danlos syndrome characterized by failure to thrive, loose skin, skeletal abnormalities, hypotonia, and hypermobile joints. Defects in forming heparin sulfate, also attached to proteins via O-xylosylation, cause congenital exostosis, an autosomal dominant disorder where patients have bony outgrowths usually at the growth plate of the long bones. Defective cartilage proteoglycan sulfation leads to achondrogenesis, diastrophic dystrophy, atelosteogenesis that manifest symptoms in cartilage and bone like cleft palate, club feet, and in the most severe cases lead to perinatal death from respiratory insufficiency.

Additionally, there are close to 20 different genetic disorders that lead to a defect in O-mannosylation. O-mannosylation defects lead to hypoglycosylation of α-dystroglycan, an important glycoprotein needed to link the intracellular cytoskeleton of muscle to the extracellular matrix. These disorders, collectively referred to as α-dystroglycanopathies, have a wide spectrum of clinical severity and encompass previously described disorders, ranging from Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, to limb-girdle muscular dystrophy.

In the neonate, clinical features of O-linked protein glycosylation defects involve the triad of muscle, eye, and brain and may include hypotonia; muscle weakness; microcornea; microphthalmia; pale, hypoplastic or absent optic nerves; colobomas; cataracts; iris hypoplasia; glaucoma; retinal dysplasia or detachment; and brain structural abnormalities including hydrocephalus, brainstem hypoplasia, cerebellar cysts, cobblestone lissencephaly, polymicrogyria, cerebellar vermis and hemisphere atrophy, hypoplasia of the pyramidal tracts, and absence of the corpus callosum. There is no specific blood or urine biochemical marker available for this group of disorders. Elevated creatine kinase is frequently noted. Muscle biopsy with specialized immunohistochemical staining may show deficient glycosylated alpha-dystroglycan and normal beta-dystroglycan. Molecular testing is needed to confirm the specific type.

Combined Glycosylation Defects

Etiology

Combined N- and O- and other glycosylation defects are important because they appear to affect trafficking in the glycosylation machinery. Several of these disorders involve defects in channels involved in activated sugar-nucleotide transport (SLCx-CDG). Some affect vesicular transport (COGx-CDG) in general. Others affect the process of sugar activation (attaching nucleotides to monosaccharides so that they can be used for glycosylation). And yet others cause abnormalities in the Golgi apparatus structure (TMEMx-CDG) that is needed to be intact for glycosylation to proceed.

Clinical Features

In the neonate, the most frequent presenting symptoms of combined glycosylation defects include neonatal microcephaly; neonatal seizures; strabismus; hypotonia; dysmorphic features, especially cutis laxa; feeding problems with growth delay; and hepatic involvement. Neonatal cholestatic hepatic failure can be the presenting or predominant symptom of a neonate with a combined defect. Encompassing a very large group of disorders, presentations are heterogeneous and include not only multisystemic diseases, but also single-system disorders such as congenital dyserythropoietic anemia type II due to SEC23B-CDG.

Glycosylphosphatidylinositol Anchor Glycosylation Defects

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