Score 99 USMLE blog: Genetic Metabolic

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Angelman Syndrome vs. Prader Willi Syndrome: Genetics and Clinical Features

Prader-Willi and Angelman syndromes are the two most common genetic disorders of imprinting. The concept of imprinting lies in the fact that the function of certain genes is dependent on their parents: maternal or paternal. Basically there is something wrong with the 15q11 region of the paternally derived chromosome in Prader Willi syndrome and that of the maternally derived chromosome in Angelman syndrome.

Prader-Willi phenotype can occur as a result of one of the following

1. Deletion of 15q11-q13 including the Prader-Willi critical region of the paternally derived chromosome 15 (most common)

2. Abnormality of the structure of Prader-Willi critical region of 15q11-q13 (for example translocation)

3. If the child has two maternally derived chromosome 15s. (Hence absence of paternal chromosome 15)

4. Mutations of imprinting control center genes (rare)

The critical region of chromosome 15 for Angelman syndrome is located very close to the Prader-Willi critical region. But, when deletion of the Angelman critical region results, it is the maternally derived chromosome that is affected.

Mechanisms leading to Angelman syndrome include the following:

1. Deletion of the 15q11-q13 including the Angelman critical region of the maternally derived chromosome 15 (most common)

2. Abnormality of the structure of the Angelman critical region of 15q11-q13 (e.g. translocation)

3. If the child has two paternally derived chromosome 15s. (Hence absence of maternal chromosome 15)

4. Mutations of imprinting control center genes (rare).

5. Mutations of the ubiquitin-protein ligase gene (UBE3A)

6. No identifiable etiologic mechanisms but a positive family history of other affected individuals and a classic phenotype

Clinical features of Prader Willi syndrome:

Newborns: hypotonia, poor sucking and swallowing, weak cry
Infancy: Delayed motor and speech development
Toddler: Hypotonia goes away! Extreme appetite leading to morbid obesity.

In addition hands and feet are noticeably small from birth, height is short and the penis and testes are hypoplastic. Patients have emotional lability and extreme temper tantrums.

Clinical features of Angelman syndrome:

Severe cognitive deficits; speech is heavily impared. Inappropriate paroxysms of laughter (happy puppets). Physical features include microcephaly, maxillary hypoplasia, large mouth, and short stature.Seizures are common. Except for case reports, all patients are infertile.

Osteogenesis Imperfecta

The term Osteogenesis imperfecta was coined by Lobstein. The term is some what self explanatory! It is one of the relatively common bone dysplasias (1 in 20000 live births). OI involves all parts of the body that contain type 1 collagen to some extent giving rise to a variety of clinical presentations. Underlying mechanism in simple words is functional or actual decrease in collagen type 1 secondary to mutations in genes (most are inherited in autosomal dominant manner) coding for the same.

Clinical features include blue sclera, triangular facies, macrocephaly, hearing loss, dentition problems, chest deformity, scoliosis, limb deformities, fractures, joint laxity, constipation, sweating and growth retardation. There are several types, some being more severe than others (classified according to Sillence Classification). Type II has the most severe clinical presentation with most babies dying in newborn period. Type I is the mildest and commonest sub-type.

Diagnosis of OI is usually made clinically and confirmed by genetic testing for mutations. Radiological tests are useful and confirmatory in many cases. Findings include: fractures, excessive callus formation and popcorn bones (multiple radiolucent areas with radiodense rims), wormian bones in the skull, enlargement of frontal and mastoid sinuses, deformities of ribs, narrow pelvis. In mild cases dual x-ray absorptiometry (DEXA) scan can be useful and will show decreased bone mineralization.

Treatment is essentially supportive. Bisphosphonates, especially pamidronic acid, are drugs that inhibit osteoclast-induced bone resorption. These are given in a cyclic manner (every few weeks) and have been shown to decrease the fracture rate (especially in type III and IV OI). Side effects of pamidronic acid include hypocalcemia (usually not severe), leukopenia, increase in bone pain (which is typically transient), and scleritis.

Other drugs with unclear roles in the treatment of OI include: Human growth hormone, teriparatide (which is human parathyroid hormone, brand name is Forteo). Bone marrow transplantation and gene therapy are being investigated. Aggressive physical therapy, occupational therapy and education of parents about injury prevention is essential.

Above article also serves as explanation to Quiz 28: 'Femur X-Ray of a 3 year old boy' on the website www.pedsquiz.com

Propionic acidemia

Propionic acidemia is an autosomal recessive disorder in which the body is unable to process certain parts of proteins and lipids. It is classified as an organic acid disorder (organic acids build up).

Diagnosis:

Symptoms appear within a few days of birth and include vomiting, poor feeding, hypotonia and lethargy. Leukocyte propionyl CoA carboxylase activity is the study required for definitive biochemical diagnosis and appropriate genetic counseling. Blood ammonia levels (elevated secondarily), Lactate levels, electrolytes, Urine ketones are other tests recommended in this condition. Anion gap will be increased due to increased unmeasured acids. ECG is recommended in all patients because of increased risk of prolonged QTc interval.

Pathophysiology:

The enzyme propionyl-CoA carboxylase is dysfunctional in propionic acidemia. Mutations in the PCCA and PCCB genes are responsible. As a result propionyl CoA accumulates in the body.

Treatment:

In acute illness - extra calories. No proteins. Once clinical condition improves can resume proteins at a very low concentration using special formulas that lack in isoleucine, valine, threonine, methionine

Breast cancer, HER2 receptors and Monoclonal antibodies

One thirds of all breast malignancies have amplification of the HER2 gene. HER2 stands for human epidermal receptor type 2. HER2 receptor is a transmembrane tyrosine kinase receptor whose stimulation leads to a number of molecular pathways associated with tumor growth and progression.

Cancers that express HER2 have poorer prognosis.

Trastuzumab also known as Herceptin is a recombinant monoclonal antibody specifically directed against the HER2 receptor and it has been shown to be improve the response rate in breast cancer patients. This antibody is used in combination with chemotherapy including doxorubicin, cyclophosphamide and paclitaxel.

Another antibody named Lapatinib (a.k.a. Tykerb) which is a 4-anililoquinazoline kinase that inhibits the tyrosine kinase domains of HER2 receptor is also being studied.

National Comprehensive Cancer Network recommends use of these agents in addition to chemotherapy for patients with HER2-positive breast cancers that are larger than 1 cm and have spread to lymphnodes.

***This topic is hot for the USMLE***

Alkaptonuria

Alkaptonuria is caused by inherited deficiency of the liver enzyme homogentisic aicd dioxygenase. This leads to accumulation of homogentisic acid, which is rapidly cleared in the kidney and excreted.

When homogentisic acid comes on contact with air, it is oxidized to form a black colored compound. Hence the urine of these patient turns black on standing. Kidneys are efficient at clearing homogentisic acid initially but eventually it gets deposited in various tissues.

The earliest symptom may be the mother noticing a black diapers. Ochronosis, which is visible deposition of the pigment in tissues usually does not occur before the fourth decade. The tissues most commonly involved include cartilage, sclera. This leads to joint problems. It is speculated that heart disease including myocardial infarction may be more common but there is not enough statistical evidence.

Smith-Lemli-Opitz syndrome/RSH syndrome

Initially described in 1964 this is an inborn error of metabolism of in the steroid synthesis pathway. This syndrome was initially called RSH after the first initial of the last names of the first 3 patients evaluated!

This syndrome is caused by a deficiency of the microsomal enzyme DHCR7(Dehydrocholesterol reductase 7), which is responsible for conversion of 7DHC to cholesterol as the last step in cholesterol synthesis. Affected children hence have low plasma cholesterol levels and elevated levels of cholesterol precursors (e.g. 7DHC).

Clinical features are variable and include llethargy, rrespiratory failure, deafness, feeding difficulties, failure to thrive, photosensitivity, mental retardation, autism, antisocial, self-destructive, and violent acts , intrauterine growth retardation (IUGR), microcephaly, broad nasal tip with anteverted nostrils, micrognathia, ptosis, squint, congenital cataracts, low-set ears, syndactyly and/or polydactyly, hypospadias or cryptorchidism in males and ambiguous genitalia in females, cleft palate and congenital cardiac defects.

X linked Recessive diseases

Adrenoleukodystrophy which leads to progressive brain damage, failure of the adrenal glands and eventually death.

Alport syndrome which includes glomerulonephritis-renal failure and deafness.

Androgen insensitivity syndrome with receptor resistance to the effect of androgens. The patient is typically a young woman (phenotypically) with XY chromosomes.

Charcot-Marie-Tooth disease which is a hereditary neuropathy.

Duchenne and Becker muscular dystrophy characterized by rapid progression of muscle degeneration, eventually leading to loss in ambulation and death.

Fabry disease- a lysosomal storage disease due to deficiency of the enzyme ceraminidase.

Fragile X syndrome resulting from expansion of a single trinucleotide gene sequence (CGG) on the X chromosome. Clinical features include long face, testicular enlargement, Mental retardation.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Hemophilia A and B (Deficiency of factor 8 and 9 respectively). Hemophilia B is also known as Christmas disease.

Hunter's Syndrome which is one of the Mucopolysachharidosis.

Kabuki syndrome with multiple congenital anomalies and mental retardation.

Lesch-Nyhan syndrome is a disorder of purine metabolism with neurologic dysfunction, cognitive and behavioral disturbances including self-mutilation.

Lowe Syndrome- Oculo-cerebro-renal syndrome.

Menkes disease with sparse and coarse hair, growth failure, and neurological symptoms.

Ornithine transcarbamylase deficiency is relatively common disorder of protein metabolism.

Red-Green color blindness, also known as daltonism.

Rett syndrome with acquired microcephaly and small hands and feet. Stereotypic, repetitive hand movements.

Wiskott-Aldrich syndrome is the classic triad of eczema, thrombocytopenia and immune deficiency.

X-linked agammaglobulinemia (XLA) also known as Bruton's disease.

X-linked ichthyosis (fish skin) is a hereditary deficiency of the steroid sulfatase (STS) enzyme.

X-linked Severe Combined Immunodeficiency (SCID); is a severe form of immunodeficiency usually causing death in the first years of life.

prGCD - plant cell expressed recombinant Glucocerebrosidase enzyme (GCD) for use in Gaucher's disease

This is a newly approved (partially approved for use by the Food and Drug Administration-FDA) drug for the treatment of patients with Gaucher's Disease.

Gaucher's disease is the most common lysosomal storage diseases in humans. It is caused by a hereditary deficiency of the enzyme glucocerebrosidase (also known as acid β-glucosidase). The enzyme acts on glucocerebroside which accumulates in its absence. Fatty material collects in the liver, kidneys, lungs, spleen, brain and bone marrow. The disease is inherited in autosomal recessive manner. The locus is on chromosome 1.

Traditionally Gaucher's disease has been classified in the following 3 types.

Type I (or non-neuropathic type) is the most common form of the disease. It occurs in 1 in 50,000 births. It is much more frequent in children of Ashkenazi Jewish heritage. Symptoms include enlarged liver and spleen. Bone marrow replacement can cause anemia, thrombocytopenia and leukopenia. The brain is usually not affected. Rarely there is lung or kidney impairment. These patients may live well into adulthood.

Type II (or acute infantile neuropathic form) typically begins in infancy and occurs in approximately 1 in 100,000 births. The diagnostic symptom of this type is extensive and progressive brain damage. Affected children do not usually live longer than 2 years of age.

Type III (the chronic neuropathic type) has a variable onset. Incidence is 1 in 100,000 births. It is characterized by slowly progressive but milder neurologic symptoms. Other major symptoms include an spleen and/or liver enlargement, seizures, bone marrow disorders and respiratory problems.

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