Tag Archives: #autosomalrecessive

Rare Genetic Diseases – MCAD

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

MCAD) – Medium Chain ActylCoA Dehydrogenase Deficiency prevents converting fats to energy especially with fasting fatty acids → acetylCoA). MCAD is inherited in an autosomal recessive manner (25% if both parents are gene carriers).

MCAD is characterized by:

  • Vomiting
  • Lethargy
  • Seizures
  • Hypoglycemia

A mutation may be found in the ACADM gene.

Inheritance: 1 in 50,000

Diagnosis:

  •  Pregnancy – HELLP

Fatty Acid Oxidation Deficiency. Diagnosis: blood/urine (blood – acylcantiines (alanocylcarnitines)

Rx: Glucose – avoid starvation L carnitine?

Medicine: Ravicti

Background: It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in their lifetime.

Rare Genetic Disease affects 1 in 200,000 people. The registry established that there are an average of 4200 cases per Rare Disease. National Organization of Rare Diseases was established in 1983 by Abbey Meyers and others.

Analysis: One of the greatest dilemmas facing the healthcare provider is when a family presents with a positive family history of a very rare genetic disease and/or syndrome [e.g. Medium Chain AcylCoA Dehydrogenase Deficiency (MCAD)] and the family wants to know from the healthcare provider:

  • Whether the disease and/or syndrome is inherited (autosomal dominant manner (50%), autosomal recessive (25% if both parents are gene carriers) or sex (X) linked (50% of males will be affected, 50% of females will be carriers), multifactorial (interaction of multiple genes with the environment, both genetic and non-genetic factors)?
  • Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family?
  • Whether the disease is caused by a Microdeletion?
  • Whether there is testing for the disease and/or syndrome?
  • If there is testing, is prenatal diagnosis and/or Preimplantation Genetic Diagnosis (PGD) available?

Furthermore, if screening and/or testing is available, the healthcare provider has the responsibility of deciding whether to recommend testing which may or may not detect patients who are carriers or affected with one or more disorders.

If a test returns as “carrier” most conditions identified will require testing the partner since the majority of the conditions tested for are inherited in an autosomal recessive manner [inheritance of one disease causing (deleterious) gene from each parent].

Since not all screening laboratories are contracted with insurance companies and panels currently offered may screen from 3 to 250 diseases, the healthcare provider will need to decide which tests to order and which laboratory to use.

However, the ACOG guideline does not set up a specific pre pregnancy panel nor recommend how many diseases or which diseases should be tested for except for those already recommended [e.g. Cystic Fibrosis, Fragile X, Spinal Muscular Atrophy (SMA), some “ethnic” panels, etc.].

Some laboratories are now offering “customized” panels developed by the healthcare provider in consultation with the laboratory based on the individual’s personal and family history and background. With the increasing availability of such panels and the reduction in the cost, the demand for larger panels and the need for interpretation of laboratory results for the healthcare provider and the patient will continue to increase.

Likewise, it can also be expected as the number of diseases tested for increases, a greater percentage of “variants of uncertain clinical significance” will also increase. Interpretation, explanation and additional recommendations for monitoring and follow-up of the individual screened and other family members will also be required.

MCAD

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

MCAD) – Medium Chain ActylCoA Dehydrogenase Deficiency prevents converting fats to energy especially with fasting fatty acids → acetylCoA). MCAD is inherited in an autosomal recessive manner (25% if both parents are gene carriers)

MCAD is characterized by:

  • Vomiting
  • Lethargy
  • Seizures
  • Hypoglycemia

A mutation may be found in the ACADM gene.

Inheritance: 1 in 50,000

Diagnosis:

  •  Pregnancy – HELLP

Fatty Acid Oxidation Deficiency. Diagnosis: blood/urine (blood – acylcantiines (alanocylcarnitines)

Rx: Glucose – avoid starvation L carnitine?

Medicine: Ravicti

Background: It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in their lifetime.

Rare Genetic Disease affects 1 in 200,000 people. The registry established that there are an average of 4200 cases per Rare Disease. National Organization of Rare Diseases was established in 1983 by Abbey Meyers and others.

Analysis: One of the greatest dilemmas facing the healthcare provider is when a family presents with a positive family history of a very rare genetic disease and/or syndrome [e.g. Medium Chain AcylCoA Dehydrogenase Deficiency (MCAD)] and the family wants to know from the healthcare provider:

  • Whether the disease and/or syndrome is inherited (autosomal dominant manner (50%), autosomal recessive (25% if both parents are gene carriers) or sex (X) linked (50% of males will be affected, 50% of females will be carriers), multifactorial (interaction of multiple genes with the environment, both genetic and non-genetic factors)?
  • Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family?
  • Whether the disease is caused by a Microdeletion?
  • Whether there is testing for the disease and/or syndrome?
  • If there is testing, is prenatal diagnosis and/or Preimplantation Genetic Diagnosis (PGD) available?

Furthermore, if screening and/or testing is available, the healthcare provider has the responsibility of deciding whether to recommend testing which may or may not detect patients who are carriers or affected with one or more disorders.

If a test returns as “carrier” most conditions identified will require testing the partner since the majority of the conditions tested for are inherited in an autosomal recessive manner [inheritance of one disease causing (deleterious) gene from each parent].

Since not all screening laboratories are contracted with insurance companies and panels currently offered may screen from 3 to 250 diseases, the healthcare provider will need to decide which tests to order and which laboratory to use.

However, the ACOG guideline does not set up a specific pre pregnancy panel nor recommend how many diseases or which diseases should be tested for except for those already recommended [e.g. Cystic Fibrosis, Fragile X, Spinal Muscular Atrophy (SMA), some “ethnic” panels, etc.].

Some laboratories are now offering “customized” panels developed by the healthcare provider in consultation with the laboratory based on the individual’s personal and family history and background. With the increasing availability of such panels and the reduction in the cost, the demand for larger panels and the need for interpretation of laboratory results for the healthcare provider and the patient will continue to increase.

Likewise, it can also be expected as the number of diseases tested for increases, a greater percentage of “variants of uncertain clinical significance” will also increase. Interpretation, explanation and additional recommendations for monitoring and follow-up of the individual screened and other family members will also be required. 

Autosomal Recessive Polycystic Kidney Disease (ARPKD)

© 2018, GENASSIST, Inc.     

By Keith S. Wexler, MBA, CFO, Business Development Director Life Sciences, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Polycystic Kidney Disease (PKD) is inherited in an autosomal dominant manner [ADPKD] – (50% risk to first degree relatives) or autosomal recessive manner [ARPKD] – (25% if both parents are gene carriers).

One of the characteristics of a disease caused by inheritance of a single deleterious gene (autosomal dominant inheritance) is variable severity.  This means that any or all children who inherit the deleterious gene (50% of children) could have milder or more severe problems related to their kidney function. 

  • Polycystic Kidney Disease has an incidence of approximately1:400 to 1:1000
  • Polycystic Kidney Disease  may be acquired

Autosomal Recessive Polycystic Kidney Disease (ARPKD) has an incidence of approximately 1 in 20,000. The condition is due to the inheritance of one disease causing (deleterious) mutation in the PKHD1 gene on the long arm of chromosome #6 (6p21.2-p12). 

Symptoms can vary from relatively mild very severe resulting in very low to no amniotic fluid in pregnancy resulting in respiratory insufficiency and pregnancy loss or early newborn demise.

When less severe, these children often experience significant kidney insufficiency often in the newborn period or the first several years of life resulting in early demise or kidney transplantation.

These infants often have cysts in the liver and may experience liver dysfunction, liver failure, bleeding abnormalities as well as feeding difficulties and recurrent infections.

Testing for most cases of autosomal dominant or autosomal recessive polycystic kidney disease is available through Invitae although Not all disease causing mutations have been identified.

Detection is estimated at approximately 80-90% for autosomal dominant disease and approximately 60% for detection of autosomal recessive disease.

Ciliopathies are a group of disorders which have many manifestations including:

  • Diabetes
  • Obesity
  • Eye abnormalities
  • Kidney disease
  • Abnormal bone development
  • Extra digits
  • Intellectual disability
  • Other neurological problems 

Most case of ADPKD (Autosomal Dominant Polycystic Kidney Disease) are due to one or more mutations in the PKD1 gene on the short arm on chromosome #16 (16p13.3) which is involved in the formation of the protein polycystin 1 (85% of cases) or the PKD2 gene on the long arm of chromosome #4 (4q21-13) which is involved in the formation or protein polycystin 2 (15% of cases).. 

If the mutation is identified in the patient then Preimplantation Genetic Diagnosis (diagnosis made on an embryo) becomes a possibility.

PKD causes multiple cysts to form in the kidneys, occasionally the liver and rarely the pancreas. Heart valve problems, abdominal wall hernias and intracerebral aneurysms can occur. 

The kidney cysts diminish kidney function eventually resulting in kidney failure.

The condition may be asymptomatic early in the course of the disease but can cause abdominal or back pain, blood in the urine, kidney stones, kidney infection, fatigue, joint pain and skin or nail abnormalities.

At least 400 mutations have been identified in the PKD1 gene [Polycystic Kidney Disease (Type I)] and over 40 mutations have been identified in the PKD2 gene.

Rarely, mutations in a third gene –PKD3 also can result in autosomal dominant PKD.

PKD can affect both the liver and kidneys and can result in serious renal problems either shortening the individual’s lifespan or resulting in kidney transplantation.

Canavan Disease

© 2018, GENASSIST, Inc.     

By Keith S. Wexler, MBA, Maternal Fetal Medicine, Prenatal Diagnosis and Biotech/Life Sciences Consultant, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Definition:

  • Microarray: Computerized analytic system for looking for specific DNA fragments associated with specific diseases (e.g. Spinal Muscular Atrophy or Tay Sachs).

Canavan Disease is a common Ashkenazi Jewish inherited disease with a carrier frequency of (1 in 40) and affects (1 in 6400) pregnancies.

Canavan Disease: Autosomal recessive inheritance (25% if both parents are gene carriers) has been described.

Canavan Disease is a fatal metabolic blood disease usually detected by age 18 months and is characterized by brain deterioration.

It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in the lifetime.

Rare Genetic Disease affects 1 in 200,000 people. The registry established that there are an average of 4200 cases per Rare Disease. National Organization of Rare Diseases established 1983 by Abbey Meyers and others got Orphan Drug Act passed 1983.

Analysis: One of the greatest dilemmas facing the healthcare provider is when a family presents with a positive family history of a very rare genetic disease and/or syndrome (e.g. Canavan Syndrome) and the family wants to know from the healthcare provider:

  • Whether the disease and/or syndrome is inherited (autosomal dominant manner (50%), autosomal recessive (25% if both parents are gene carriers) or sex (X) linked (50% of males will be affected, 50% of females will be carriers), multifactorial (interaction of multiple genes with the environment, both genetic and non-genetic factors)?
  • Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family?
  • Whether the disease is caused by a Microdeletion?
  • Whether there is testing for the disease and/or syndrome?
  • If there is testing, is prenatal diagnosis and/or Preimplantation Genetic Diagnosis (PGD) available?

Furthermore, if screening and/or testing is available, the healthcare provider has the responsibility of deciding whether to recommend testing which may or may not detect patients who are carriers or affected with one or more disorders.

If a test returns as “carrier” most conditions identified will require testing the partner since the majority of the conditions tested for are inherited in an autosomal recessive manner [inheritance of one disease causing (deleterious) gene from each parent].

Since not all screening laboratories are contracted with insurance companies and panels currently offered may screen from 3 to 250 diseases, the healthcare provider will need to decide which tests to order and which laboratory to use.

However, the ACOG guideline does not set up a specific pre pregnancy panel nor recommend how many diseases or which diseases should be tested for except for those already recommended [e.g. Cystic Fibrosis, Fragile X, Spinal Muscular Atrophy (SMA), some “ethnic” panels, etc.].

Some laboratories are now offering “customized” panels developed by the healthcare provider in consultation with the laboratory based on the individual’s personal and family history and background.

With the increasing availability of such panels and the reduction in the cost, the demand for larger panels and the need for interpretation of laboratory results for the healthcare provider and the patient will continue to increase.

Likewise, it can also be expected as the number of diseases tested for increases, a greater percentage of “variants of uncertain clinical significance” will also increase.

Interpretation, explanation and additional recommendations for monitoring and follow-up of the individual screened and other family members will also be required.

Anticipation of Disease

© 2017, GENASSIST, Inc.     

By Keith S. Wexler, MBA, Maternal Fetal Medicine, Prenatal Diagnosis and Biotech/Life Sciences Consultant, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Some diseases appear to repeat in some families (familial) and become more severe and occur at a younger age from generation to generation. This is described in the genetic community as “Anticipation”.

Some of these disorders have a clear genetic pattern of inheritance e.g. Myotonic Dystrophy and Huntington’s Disease inherited in an Autosomal Dominant manner and Fragile X and Spinal-Bulbar Muscular Atrophy inherited in a sex linked (X Linked) manner.

Friedrich’s Ataxia can be inherited in an Autosomal Recessive manner and the Spinocerebellar Ataxias or Dyskeratosis Congenita can be inherited in an Autosomal Dominant, Autosomal Recessive or sex linked (X Linked) manner.

All of these diseases may demonstrate “Anticipation”.

These disease may demonstrate expansions* of Triplet Trinucelotide repeats (e.g. CAG, CTG, GTG, GAG), Pentanucleotide repeats (e.g. TGGAA, ATTCT) or Telomeric Repeats (e.g. TTA, GGG). Expansions of these repeats have been associated with human disease(s) and in some cases “Anticipation”.

  • *Adenine – A
  • Cytosine – C
  • Guanine – G
  • Thymine – T

Summary:

Some disorders with multiple or uncertain modes of inheritance also appear to demonstrate “Anticipation” and have a genetic component involved [e.g. certain cancers (breast, pancreatic), Crohn’s Disease, Behcet’s Syndrome and Meniere’s Disease.

 

 

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