What is Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency (SSADHD)?

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited disorder of GABA metabolism characterized by developmental delays and neurologic abnormalities that appear in infancy. Neurologic abnormalities usually appear by 1-2 years of age and include developmental delay and intellectual disability. Seizures may develop in infancy or later in childhood. The disorder is unique in the accumulation of two neuromodulatory species in the physiological fluids of patients, including the inhibitory neurotransmitter GABA and the GABA-analog, gamma-hydroxybutyric acid (GHB). The normal metabolic pathway of GABA includes two enzymes: GABA transaminase followed by SSADH. In the absence of SSADH, the intermediate succinic semialdehyde accumulates and is converted to GHB, a compound with complex and incompletely-defined roles in the central nervous system, but an agent with high-affinity binding sites.

The key symptoms of SSADHD include:

• Non-progressive encephalopathy (although a subset of patients may have a progressive phenotype)
• Decreased muscle tone in the arms and/or legs (hypotonia)
• Intellectual disability
• Ataxia
• Striking absence of formalized speech
• Neuropsychiatric morbidity prominently occurring in late childhood through adolescence, including OCD and ADHD
• Seizures
• Accumulation of GABA and GHB in physiological fluids

How many people have SSADHD?

SSADHD is estimated to occur in 1 per 1,000,000 births worldwide, and is higher in certain geographic locations such as the Mideast, Turkey, and Greece. As of this writing, approximately 180 patients have been reported in the primary literature (Attri et al 2017). The figure indicates the panethnic nature of patients in terms of geographic locations. Diagnosis based upon clinical features is impossible (due to the nonspecific neurological features). The initial diagnosis is made through the detection of elevated urinary GHB achieved using routine organic acid analysis. This must be followed-up with either repeat urine organic acid analysis and, preferably, molecular diagnostics since GHB is employed in illicit settings, as well as in an increasing number of clinical situations, including narcolepsy, fibromyalgia, and other experimental uses.

What causes SSADHD?

SSADHD is caused by mutations (or changes) in the ALDH5A1 gene that makes the enzyme succinic semialdehyde dehydrogenase. SSADH is one of two enzymes active in the catabolism of the major inhibitory neurotransmitter, GABA. In the absence of SSADH, the accumulated succinic semialdehyde (the product of the GABA transaminase reaction) is converted to GHB. Mutations in ALDH5A1 result in an inactive SSADH enzyme and accumulation of GABA and GHB, and several other metabolites related to both compounds. Accumulation of neuromodulatory compounds, under a variety of permutations, is believed in turn to cause developmental delay and intellectual disability. Neurologic symptoms are associated with accumulation of neurotransmitters in the brain that can be seen on specialized MRI brain scans. SSADHD is an inherited autosomal recessive disorder. Affected individuals inherit two copies of the mutated or changed ALDH5A1 gene, one from each parent. Therefore the parents are "carriers" of SSADHD, meaning that they have one normal functioning copy and one nonfunctioning copy of the gene. With each pregnancy, carriers of SSADHD have a 1 in 4 or 25% chance of having a child with SSADHD.

How is SSADHD diagnosed?

The first step in diagnosis is the identification of increased GHB in the urine organic acid profile. This is subsequently confirmed by genetic testing of the ALDH5A1 gene. The potential for newborn screening through determination of bloodspot GABA levels in under active investigation.

What is the treatment for SSADHD?

There is no curative treatment for SSADHD and targeted therapeutics are lacking. Current medications are palliative (antiepileptics for seizures, various neuroleptics for OCD). Historically, the antiepileptic vigabatrin (SabrilR) has been employed as a first line intervention. As an irreversible inhibitor of GABA transaminase, vigabatrin is rational, yet it is predicted (and documented) to increase GABA in the central nervous system. The latter may be contraindicated in an already hyperGABAergic syndrome such as SSADHD.

More Information:

OMIM: Succinic semialdehyde dehydrogenase (# 271980)

Associated Websites and Patient Support groups:

• SSADH Association: http://www.ssadh.net/ (USA)
• De Neu: http://www.deneu.org (Spain)
• Unser Weg Mit SSADH: https://ssadh.wordpress.com/english-version/ (Germany)
• http://www.pharmacy.wsu.edu/facultystaff/bios/gibson.km.html

Ongoing Clinical Trials

Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency

Selected citations

• Gibson KM, Sweetman L, Nyhan WL, Jakobs C, Rating D, Siemes H, Hanefeld F. Succinic semialdehyde dehydrogenase deficiency: an inborn error of gamma-aminobutyric acid metabolism. Clin Chim Acta. 1983 Sep 15;133(1):33-42.
• Chambliss KL, Hinson DD, Trettel F, Malaspina P, Novelletto A, Jakobs C, Gibson KM. Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria). Am J Hum Genet. 1998 Aug;63(2):399-408.
• Hogema BM, Gupta M, Senephansiri H, Burlingame TG, Taylor M, Jakobs C, Schutgens RB, Froestl W, Snead OC, Diaz-Arrastia R, Bottiglieri T, Grompe M, Gibson KM. Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nat Genet. 2001 Oct;29(2):212-6.
• Gupta M, Greven R, Jansen EE, Jakobs C, Hogema BM, Froestl W, Snead OC, Bartels H, Grompe M, Gibson KM. Therapeutic intervention in mice deficient for succinate semialdehyde dehydrogenase (gamma-hydroxybutyric aciduria). J Pharmacol Exp Ther. 2002 Jul;302(1):180-187
• Vogel KR, Ainslie GR, Schmidt MA, Wisor JP, Gibson KM. mTOR Inhibition Mitigates Molecular and Biochemical Alterations of Vigabatrin-Induced Visual Field Toxicity in Mice. Pediatr Neurol. 2017 Jan;66:44-52.e1. doi: 10.1016/j.pediatrneurol.2016.09.016.
• Vogel KR, Ainslie GR, Gibson KM. mTOR inhibitors rescue premature lethality and attenuate dysregulation of GABAergic/glutamatergic transcription in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism. J Inherit Metab Dis. 2016 Nov;39(6):877-886.
• Vogel KR, Ainslie GR, Pearl PL, Gibson KM. Aberrant mTOR signaling and disrupted autophagy: The missing link in potential vigabatrin-associated ocular toxicity? Clin Pharmacol Ther. 2016 Nov 19. doi: 10.1002/cpt.581. [Epub ahead of print]
• Attri SV, Singhi P, Wiwattanadittakul N, Goswami JN, Sankhyan N, Salomons GS, Roullet J-B, Hodgeman R, Parviz M, Gibson KM, Pearl PL. Incidence and Geographic Distribution of Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency. Inherit. Metab. Dis., Rep. 2016 Nov 5. [Epub ahead of print]
• Malaspina P, Roullet J-B, Pearl PL, Ainslie GR, Vogel KR, Gibson KM. Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism. Int., 2016;99:72-84
• Schreiber JM, Pearl PL, Dustin I, Wiggs E, Barrios E, Wassermann EM, Gibson KM, Theodore WH. Biomarkers in a taurine trial for succinic semialdehyde dehydrogenase deficiency. JIMD Rep. 2016;30:81-87.
• Johansen SS, Wang X, Sejer Pedersen D, Pearl PL, Roullet J-B, Ainslie GR, Vogel KR, and Gibson KM. Gamma-Hydroxybutyrate (GHB) Content in Hair Samples Correlates Negatively with Age in Succinic Semialdehyde Dehydrogenase Deficiency. Inherit. Metab. Dis., 2017 Feb 18. doi: 10.1007/8904_2017_3. [Epub ahead of print]

What is Sjögren-Larsson Syndrome?

Sjögren-Larsson Syndrome (SLS) is an inherited disorder characterized by skin abnormalities (ichthyosis) and neurologic abnormalities that appear in infancy. Ichthyosis appears as a dry, scaly skin condition, often with redness and itchiness. Neurologic abnormalities usually appear by 1-2 years of age and include tight muscles (spasticity) that impair walking, developmental delay and intellectual disability. Seizures may develop in infancy or later in childhood. Light sensitivity (photophobia) is common and changes in the back of the eye (retina) are often seen.

The key symptoms of SLS include:

• Dry, scaly skin (ichthyosis) that is usually present at birth and is often itchy
• Increased muscle tone in the arms and/or legs (spasticity)
• Intellectual disability
• Eye abnormalities and light sensitivity
• Speech difficulties
• Seizures

How many people have Sjögren-Larsson Syndrome?

SLS is estimated to occur in 1 per 250,000 births worldwide and higher in certain geographic locations such as Sweden and the Mideast.

What causes Sjögren-Larsson Syndrome?

SLS is caused by mutations (or changes) in the ALDH3A2 gene that makes the enzyme fatty aldehyde dehydrogenase (FALDH). FALDH is involved in the transformation of fatty aldehydes and fatty alcohols to fatty acids in our body. The gene mutations result in an inactive FALDH enzyme and accumulation of fatty aldehydes and alcohols. This is believed in turn to cause disruption in the skin-water barrier, leading to increased water loss causing dry, scaly skin, and to neurological abnormalities of spasticity, developmental delay and intellectual disability. Neurologic symptoms are associated with accumulation of lipids in the brain that can be seen on specialized MRI brain scans.

SLS is an inherited autosomal recessive disorder. Affected individuals inherit two copies of the mutated or changed ALDH3A2 gene, one from each parent. Therefore the parents are "carriers" of SLS, meaning that they have one normal functioning copy and one nonfunctioning copy of the gene. With each pregnancy, carriers of SLS have a 1 in 4 or 25% chance of having a child with SLS.

How is Sjögren-Larsson Syndrome diagnosed?

SLS is diagnosed by measuring deficient FALDH enzyme activity in cultured skin cells or by genetic testing of the ALDH3A2 gene.

What is the treatment for Sjögren-Larsson Syndrome?

There is no curative treatment for SLS. The treatment of ichthyosis may include the use of retinoids, moisturizing lotions and keratolytic agents (peeling agent that softens and sheds the outer layer of skin). Spasticity can be treated with Botox injections and surgery. Seizures usually respond to anti-convulsant medications. All other treatments are symptomatic.

More Information:

OMIM.org: Sjögren-Larsson Syndrome

What is Smith-Lemli-Opitz Syndrome?

Smith-Lemli-Opitz Syndrome (SLOS) is an inherited disorder in which affected individuals are impaired in their ability to make cholesterol. Cholesterol is important for maintaining the normal functions of cells in the body and brain. It also plays a role in early human development.

The signs and symptoms of SLOS can be different from person to person. Most individuals with SLOS have birth defects and intellectual disability. Mildly affected individuals may only have subtle learning disabilities and physical abnormalities whereas severely affected individuals may have many of the features listed below:

• Small head size
• Intellectual disability and/or learning difficulties
• Hearing loss
• Eye abnormalities (cataracts and ptosis of eyelids)
• Feeding difficulties
• Cleft palate
• Poor growth and appetite
• Heart defects
• Breathing difficulties
• Polydactyly (extra fingers and toes)
• Genital abnormalities
• Webbed toes

How many people have Smith-Lemli-Opitz Syndrome?

It is estimated that approximately 1 in 20,000 babies are born with SLOS. SLOS has been found more frequently in Whites, African Americans and Hispanics, and less frequently in Asians. Males and females are equally affected.

What causes Smith-Lemli-Opitz Syndrome?

SLOS is caused by a mutation or change in a gene. Genes are units of DNA, our bodies' instruction manuals for growth and development, and are inherited from our mother and father at conception. In SLOS, the gene that has been changed or mutated is called the DHCR7 gene (DHCR7). This gene is responsible for making the enzyme 7-dehydrocholesterol reductase. This enzyme is needed to carry out the final step of cholesterol production in our bodies, converting 7-dehydrocholesterol (7DHC) to cholesterol. Mutations or changes in the DHCR7 gene prevent the body from making all the cholesterol that it needs. This also leads to a buildup of 7DHC in the body, since it is unable to be converted to cholesterol normally.

SLOS is an inherited autosomal recessive disorder. Affected individuals inherit two copies of the mutated or changed gene, one from each parent. Therefore the parents are "carriers" of SLOS, meaning that they have one normal functioning copy and one non-functioning copy of the DHCR7 gene. With each pregnancy, carriers of SLOS have a 1 in 4 (or 25%) chance of having a child with SLOS.

How is Smith-Lemli-Opitz Syndrome diagnosed?

SLOS is typically diagnosed by a blood test that measures the amount of cholesterol and 7-dehydrocholesterol (7DHC) in the blood. Since individuals with SLOS have a lowered capacity to make cholesterol, we expect cholesterol levels to be low and 7DHC level to be high. However, in some cases, cholesterol levels can be in the normal range. Genetic testing can also be done to confirm the diagnosis and to identify the specific changes in the DHCR7 gene that cause SLOS in that particular individual. When this information is known, testing other family members and prenatal testing in future pregnancies is also available.

What is/Is there treatment for Smith-Lemli-Opitz Syndrome?

There is currently no proven treatment for SLOS. Many individuals are given cholesterol supplementation or a high cholesterol diet, and others take simvastatin. Simvastatin has not been proven to be effective and is still considered investigational therapy that normally is not prescribed in SLOS outside of a research protocol.

More Information:

OMIM.org: Smith-Lemli-Opitz Syndrome

What is Sitosterolemia?

Sitosterolemia is a rare inherited disease characterized by storage of plant sterols. Affected individuals have abnormally high concentrations of plant sterols (phytosterols) in blood and various tissues due to hyper-absorption from the intestine and reduced excretion from the liver. The plant sterols include sitosterol, stigmasterol, and campesterol. Individuals with Sitosterolemia also have moderate to high blood cholesterol concentrations since plant sterols and cholesterol are absorbed in the same way by the body. Plant sterols and cholesterol build up in the arteries and in tendons causing swellings (xanthomas) in individuals with Sitosterolemia. Sitosterolemia is characterized by premature thickening of the artery walls due to plaque and fat build up. The build-up of plaque can lead to early heart disease. The full clinical spectrum of the disease is not known, but the commonly observed symptoms are listed below.

Common Symptoms Include:

• Tendon and tuberous xanthomas that occur in unusual locations (e.g., heels, knees, elbows, buttocks)
• Hemolysis and platelet abnormalities (e.g., hemolytic anemia, stomatocytes and macrothrombocytopenia)
• Premature coronary atherosclerosis
• Increased cholesterol concentration in a child without a family history of heart disease or elevated cholesterol

Who gets Sitosterolemia?

Sitosterolemia is a very rare disease. There have been approximately 80 patients worldwide diagnosed with Sitosterolemia. It can affect Individuals of all ages, ethnicities and sex.

What causes Sitosterolemia?

We normally consume plant sterols in our diet. These plant sterols enter the intestinal cells, but then are pumped back out into the gut for disposal to keep plant sterols out of the body. Sitosterolemia is caused by changes (mutations) in the ABCG8 and ABCG5 genes. These two genes code for proteins that normally pump plant sterols out of intestinal cells and liver cells. The changes in these genes result in abnormal proteins that are unable to do their job correctly. Therefore, high concentrations of plant sterols accumulate throughout the body.

Sitosterolemia is an inherited autosomal recessive genetic condition. Affected individuals inherit two copies of the mutated ABCG8 or ABCG5 genes, one from each parent. Therefore, the parents are "carriers" of Sitosterolemia, meaning that they have one normal functioning copy and one non-functioning copy of the genes. With each pregnancy, carriers of Sitosterolemia have a 1 in 4 or 25% chance of having a child with the disease.

How is Sitosterolemia diagnosed?

Sitosterolemia is diagnosed by measuring elevated plant sterols in the blood, including sitosterol, campesterol and stigmasterol. Normal cholesterol testing will not diagnose Sitosterolemia because it cannot distinguish among the different sterols. DNA analysis of the ABCG5 and ABCG8 genes can be helpful in detecting mutations and confirming the diagnosis, but such testing is not routinely available.

What is/Is there treatment for Sitosterolemia?

The primary goal is of treatment is to reduce the concentration of plant sterols in the blood (to be below 1 mg/dl, if possible). Sitosterolemia can be managed by restricting foods that are high in concentrations of plant sterols and shellfish sterols and by pharmacologic therapy. Foods with high plants sterols include vegetable oils, nuts, seeds and chocolate. The drug ezetimibe is effective in decreasing the plant sterol concentration in blood. Cholestryramine has been helpful for some individuals. There are some margarines and medications enriched with plant sterols or stanols (e.g. sitostanol and campestanol) that are often prescribed as a treatment for people with hypercholesterolemia; it is important for individuals with Sitosterolemia to avoid ingesting these preparations.

More Information:

OMIM.org: Sitosterolemia

What is Mevalonate Kinase Deficiency?

Mevalonate Kinase Deficiency (MKD) is an autosomal recessive inherited disorder caused by deficiency of the enzyme mevalonate kinase (ATP: mevalonate 5-phosphotransferase) causing a defect in cholesterol biosynthesis. This deficiency results in two distinct types of diseases: mevalonic aciduria (MVA), the severe form of MKD, and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), a milder form of MKD.

• MVA is characterized by delayed physical and mental development (intellectual disability), failure to thrive, recurrent episodes of fever with vomiting and diarrhea, enlarged liver, spleen and lymph nodes, microcephaly (small head size), cataract, low muscle tone, short stature, distinct facial features, ataxia (balance problems), and anemia.
   
• HIDS is characterized by recurrent episodes of fever associated with swollen lymph nodes, joint pain, gastrointestinal issues and skin rash.

How many people have Mevalonate Kinase Deficiency?

MKD is very rare. Approximately 30 individuals have been reported with MVA and more than 180 individuals have been reported with HIDS worldwide.

What causes Mevalonate Kinase Deficiency?

MKD is caused by a mutation or change in the MVK gene. The MVK gene is responsible for producing an enzyme called mevalonate kinase. This enzyme plays an important role in converting mevalonic acid to cholesterol, other sterols and isoprenoids (all mevalonate derivatives), which are all involved in the normal functions of cells in our body. If the enzyme mevalonate kinase is unable to convert mevalonic acid to other chemicals the body needs, mevalonic acid will accumulate in body fluids and mevalonic acid derivatives will not be made. The lack of production of certain mevalonate derivatives is thought to cause the disease. The exact nature of these derivatives still needs to be characterized.

MKD is an inherited autosomal recessive disorder. Affected individuals inherit two copies of the mutated or changed MVK gene, one from each parent. Therefore the parents are “carriers” of MKD, meaning that they have one normal functioning copy and one nonfunctioning copy of the gene. With each pregnancy, carriers of MKD have a 1 in 4 or 25% chance of having a child with MKD.

How is Mevalonate Kinase Deficiency diagnosed?

Individuals with MVA will usually have elevated amount of mevalonic acid metabolites in the urine, blood, and cerebrospinal fluid. The initial diagnostic test is often a urine organic acid analysis. The diagnosis should be confirmed by measurement of enzyme activity and/or DNA mutation analysis. Those with HIDS often have normal mevalonic acid metabolites, especially between episodes, so that DNA mutation analysis is the diagnostic test of choice in that group, since IgD levels are not always elevated and enzyme activity measurement for this condition is not widely available and may not always distinguish HIDS from carriers or unaffected individuals.

What is/Is there treatment for Mevalonate Kinase Deficiency?

Treatment for MVA at this time should be considered supportive and investigational. There is one report of a child receiving a liver transplant followed by a hematopoietic stem cell transplant that seems to have shown improvement. Medications that modify the inflammatory response are increasingly being used for HIDS, but this use is off-label.

More Information:

OMIM.org: Mevalonate kinase deficiency

OMIM.org: Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)

What is Cerebrotendinous Xanthomatosis?

Cerebrotendinous Xanthomatosis (CTX) is an inherited disorder in which affected individuals do not make bile acids normally. Affected individuals are unable to make normal amounts of a bile acid, chenodeoxycholic acid (CDCA), and therefore chemicals that are supposed to be converted to CDCA accumulate in various parts of the body. CTX is characterized by childhood diarrhea, cataracts and tendon xanthomas, which are soft bumps under the skin made up of yellow fatty deposits. As children grow older, they may lose mental capability and begin to show signs of abnormal movements and balance. The symptoms of CTX can vary widely between affected individuals.

Common symptoms include:

• Cataracts
• Tendon xanthomas
• Progressive abnormal movements and balance problems
• Cholesterol deposits in the brain
• Intellectual disability
• Chronic diarrhea
• Prolonged jaundice as a baby
• Psychiatric symptoms
• Seizures
• Degeneration of parts of the brain
• Premature atherosclerosis

How many people have Cerebrotendinous Xanthomatosis?

CTX is estimated to occur in 1 in 50,000 individuals worldwide and is more commonly seen in the Moroccan Jewish population with an incidence of 1 in 108 individuals in that group, as well as being more common in the Druze.

What causes Cerebrotendinous Xanthomatosis?

CTX is caused by a mutation or change in the CYP27A1 gene, (CYP27A1), which makes the enzyme sterol 27-hydroxylase. This enzyme helps in the formation of bile acids, which are important for fat absorption in our bodies, from cholesterol. Mutations or changes in the CYP27A1 gene cause accumulation or storage of cholesterol-like substances in the blood, nerve cells, and the brain.

CTX is an inherited autosomal recessive disorder. Affected individuals inherit two copies of the mutated or changed gene, one from each parent. Therefore the parents are "carriers" of CTX, meaning that they have one normal functioning copy and one nonfunctioning copy of the CYP27A1 gene. With each pregnancy, carriers of CTX have a 1 in 4 or 25% chance of having a child with CTX.

How is Cerebrotendinous Xanthomatosis diagnosed?

CTX is diagnosed based on clinical features and blood testing. Abnormalities seen in the blood in individuals with CTX include high levels of cholestanol (a cholesterol-like metabolite), decreased chenodeoxycholic acid, and increased concentrations of certain bile alcohols. Genetic testing for the gene associated with CTX, CYP27A1 is also available to confirm the diagnosis and allow carrier and prenatal testing.

What is/Is there treatment for Cerebrotendinous Xanthomatosis?

Oral CDCA replacement therapy, available in the US as Chenodal, has been shown to be an effective treatment and is prescribed off-label. Cholic acid may also be effective in CTX, but there is much less experience using this medication.

More Information:

OMIM.org: Cerebrotendinous Xanthomatosis

What is Methylsterol Oxidase Deficiency?

Methylsterol oxidase deficiency (MOD) is a genetic disorder characterized by a combination of symptoms involving skin, brain, eyes and joints. The key symptoms of MOD include:

• severe skin disease
• developmental delay
• congenital cataracts
• small head size (microcephaly)
• growth delay
• joint pain (arthralgias)

Some symptoms may be present at birth or early infancy. Other symptoms develop later in childhood.

How many people have Methylsterol Oxidase Deficiency?

The incidence of MOD is not known. The disease has only been known for a few years and very few patients have been identified.

What causes Methylsterol Oxidase Deficiency?

MOD is caused by changes (mutations) in the SC4MOL gene. This gene makes an enzyme called methylsterol oxidase, which is used by the body to make certain fats (sterols) such as cholesterol. Individuals with MOD have a missing or non-functional methylsterol oxidase enzyme that cannot metabolize methylsterols, which accumulate in the body. It is thought that increases in methylsterols are responsible for the symptoms of MOD.

MOD is a genetic disease that is inherited as an autosomal recessive disorder. Affected individuals inherit two copies of the mutated or changed SC4MOL gene, one from each parent. Therefore, the parents are "carriers" of MOD, meaning that they have one normal functioning copy and one non-functioning copy of the gene. With each pregnancy, carriers of MOD have a 1 in 4 (or 25%) chance of having a child with MOD.

How is Methylsterol Oxidase Deficiency diagnosed?

MOD is diagnosed by detecting elevated levels of methylsterols in blood or by sequencing the SC4MOL gene.

What is the treatment for Methylsterol Oxidase Deficiency?

There is no cure for MOD and the best treatment for symptoms is still not established. One patient has shown improvement in skin symptoms when treated with a statin drug and application of an ointment containing cholesterol and statin. It is not known whether this experimental treatment works on all patients. Other treatments using conventional medications are done for individual symptoms as they arise.

What are Dolichol Metabolism Disorders?

Dolichol Metabolism Disorders (DMDs) consist of a group of rare genetic diseases of dolichol metabolism. Dolichols are fatty (lipid) molecules that are needed for attaching sugars to proteins, forming glycoproteins. Glycoproteins are important for the function of many tissues and organs. Individuals with DMDs have deficiency of an enzyme that is necessary for making dolichols, which results in failure to make glycoproteins. The lack of glycoproteins in DMD individuals causes one or more symptoms.

Common symptoms include:

• Facial abnormalities
• Brain abnormalities
• Convulsions
• Low muscle strength
• Tight leg muscles and difficulty walking (spasticity)
• Problems with balance
• Eye abnormalities, cataracts or blindness
• Feeding problems
• Growth delay
• Liver function abnormalities
• Heart failure
• Frequent infections
• Dry skin
• Bone abnormalities

Symptoms of DMDs usually start in infancy or childhood, but can affect individuals of all ages, ethnicities and sex.

What causes Dolichol Metabolism Disorders?

DMDs are genetic diseases that are caused by changes (mutations) in one of 7 genes that normally make an enzyme necessary for dolichol synthesis or its metabolism. Children are born with this enzyme deficiency. The mutations or changes in these genes causes deficient or abnormal glycoproteins. The deficient glycoproteins cannot do their job correctly in the body and result in medical symptoms.

DMDs are inherited as an “autosomal recessive” disorder, meaning affected individuals must have two copies of a DMD gene to have the disease. Affected individuals inherit one DMD gene from each parent. Therefore, the parents are "carriers" of DMD, meaning that they have one normal functioning copy of the gene and one non-functioning DMD gene. With each pregnancy, DMD carriers have a 1 in 4 (or 25%) chance of both passing along their DMD gene and having a child with DMD.

How many people have a Dolichol Metabolism Disorder?

The incidence of DMD is not known. These diseases have only been known for a few years and very few patients have been identified.

How are Dolichol Metabolism Disorders diagnosed?

DMDs are diagnosed by finding reduced levels of glycoproteins in blood and demonstrating mutations in one of the DMD genes.

What is the treatment for Dolichol Metabolism Disorders?

There is no cure for DMDs and specific treatments are not yet available. Symptoms are treated as they arise using standard therapies.

What are Peroxisome Biogenesis Disorders?

Peroxisome Biogenesis Disorders (PBDs; also known as Zellweger Spectrum Disorders) are a group of rare genetic diseases that have impaired formation (biogenesis) of peroxisomes. Peroxisomes are vesicle-like structures within our cells that contain many enzymes needed for metabolism. People with PBDs cannot put enzymes or proteins into peroxisomes where they normally work and often have a decreased number of peroxisomes. Consequently, they have impaired metabolism of certain lipids (fats), amino acids, hydrogen peroxide, bile acids and other compounds. The abnormal metabolism causes impaired function of many tissues and organs. Individuals with PBDs have one or more symptoms.

Common symptoms include:

• Distinctive facial appearance
• Brain abnormalities
• Convulsions
• Low muscle strength
• Delay in achieving developmental/intellectual milestones
• Tight leg muscles and difficulty walking (spasticity)
• Eye abnormalities, cataracts or blindness
• Deafness or hearing impairment
• Feeding problems
• Adrenal gland failure
• Growth delay
• Liver function abnormalities
• Bone abnormalities and osteoporosis

Some symptoms of PBDs begin during fetal development and are evident at birth. Most other symptoms are apparent in early infancy or childhood, but can affect individuals of all ages, ethnicities and sex.

What causes Peroxisome Biogenesis Disorders?

PBDs are genetic diseases that are caused by mutations (changes) in genes that normally help form functional peroxisomes. Children are born with this genetic deficiency. The mutations in these genes cause deficient transport of enzymes and proteins into peroxisomes. The abnormal peroxisomes cannot do their job correctly in the body and result in medical symptoms.

PBDs are inherited as an "autosomal recessive" disorder, meaning affected individuals must have two copies of a mutated PBD gene to have the disease. Affected individuals inherit one PBD gene from each parent. Therefore, the parents are "carriers" of PBD, meaning that they have one normal functioning copy of the gene and one non-functioning PBD gene. With each pregnancy, PBD carriers have a 1 in 4 (or 25%) chance of both passing along their PBD gene and having a child with PBD. Parents of PBD children usually do not know they are carriers of a PBD gene until they have a child born with this disease.

How many people have a Peroxisome Biogenesis Disorder?

The incidence of PBD is not precisely known, but a best estimate is that about 1 in 25,000 births results in PBD. The rare incidence of PBD means that relatively few individuals with PBD will be diagnosed and identified every year.

How are Peroxisome Biogenesis Disorders diagnosed?

PBDs are diagnosed by finding abnormal peroxisomal metabolites in the blood or urine of individuals suspected to have a PBD based on their clinical symptoms. Often, elevated very long-chain fatty acids and reduced levels of plasmalogen lipids are detected. DNA studies are then necessary to identify which PBD gene is mutated. Methods to identify infants with PBD by screening newborn babies for elevated very long-chain fatty acids are starting to be applied and will become more widespread in the near future. This will allow almost all infants with PBD to be diagnosed, even before they develop some of the symptoms, and lead to a more accurate estimate of PBD incidence.

What is the treatment for Peroxisome Biogenesis Disorders?

Symptoms are treated as they arise using standard therapies. There is no cure for PBDs and specific treatments that target the underlying genetic defect are not yet available. Research offers hope that some of the symptoms will have improved treatments in the future.