The diagnosis of short-chain acyl-coenzyme A dehydrogenase deficiency is based on the following:

- Newborn screening test

- Genetic testing

- Urine test

The differential diagnosis for short-chain acyl-coenzyme A dehydrogenase deficiency is: ethylmalonic encephalopathy, mitochondrial respiratory chain defects and "multiple" acyl-CoA dehydrogenase deficiency.

There are several treatments available for bleeding due to factor X deficiency, however a specifi FX concentrate is not available (2009).

1. Prothrombin complex concentrate (PCC) supplies FX with a risk of thrombosis.

2. Fresh frozen plasma (FFP): This is relatively inexpensive and readily available. While effective this treatment carries a risk of blood-borne viruses and fluid overload.

3. If vitamin K levels are low, vitamin K can be supplied orally or parenterally.

Treatment of FX deficiency in amyloidosis may be more complex and involve surgery (splenectomy) and chemotherapy.

Blood tests are needed to differentiate FX deficiency from other bleeding disorders. Typical are normal thrombin time, prolonged prothrombin time (PT) and prolonged partial thromboplastin time(PTT). FX antigen and its coagulant activity can be used to classify the severity of the condition:

1. Type I has low levels of FX antigen and activity.

2. Type II has low coagulant activity but normal or borderline FX antigen levels.

The FX (F10) gene is found on chromosome 13q34. Heterogeneous mutations have been described in FX deficient patients.

Diagnosis of Molybdenum cofactor deficiency includes early seizures, low blood levels of uric acid, and high levels of sulphite, xanthine, and uric acid in urine. Additionally, the disease produces characteristic MRI images that can aid in diagnosis.

In 2009, Monash Children's Hospital at Southern Health in Melbourne, Australia reported that a patient known as Baby Z became the first person to be successfully treated for molybdenum cofactor deficiency type A. The patient was treated with cPMP, a precursor of the molybdenum cofactor. Baby Z will require daily injections of cyclic pyranopterin monophosphate (cPMP) for the rest of her life.

No treatment is available for most of these disorders. Mannose supplementation relieves the symptoms in PMI-CDG (CDG-Ib) for the most part, even though the hepatic fibrosis may persist. Fucose supplementation has had a partial effect on some SLC35C1-CDG (CDG-IIc or LAD-II) patients.

A 1999 retrospective study of 74 cases of neonatal onset found that 32 (43%) patients died during their first hyperammonemic episode. Of those who survived, less than 20% survived to age 14. Few of these patients received liver transplants.

Individuals presenting with Type III galactosemia must consume a lactose- and galactose-restricted diet devoid of dairy products and mucilaginous plants. Dietary restriction is the only current treatment available for GALE deficiency. As glycoprotein and glycolipid metabolism generate endogenous galactose, however, Type III galactosemia may not be resolved solely through dietary restriction.

Those affected with deficiency of the interleukin-1–receptor antagonist can have diagnosis achieved via noting an increase of erythrocyte sedimentation rate, as well as the following:

- Genetic test

- Radiological findings

- Clinical findings

There is no treatment for MKD. But, the inflammation and the other effects can be reduced to a certain extent.

- IL-1 targeting drugs can be used to reduce the effects of the disorder. Anakinra is antagonist to IL-1 receptors. Anakinra binds the IL-1 receptor, preventing the actions of both IL-1α and IL-1β, and it has been proved to reduce the clinical and biochemical inflammation in MKD. It can effectively decreases the frequency as well as the severity of inflammatory attacks when used on a daily basis. Disadvantages with the usage of this drug are occurrence of painful injection site reaction and as the drug is discontinued in the near future the febrile attacks start. (Examined in a 12-year-old patient).

- Canakinumab is a long acting monoclonal antibody which is directed against IL-1β has shown to be effective in reducing both frequency and severity in patients suffering from mild and severe MKD in case reports and observational case series. It reduces the physiological effects but the biochemical parameter still remain elevated (Galeotti et al. demonstrated that it is more effective than anakinra –considered 6 patients suffering from MKD).

- Anti-TNF therapy might be effective in MKD, but the effect is mostly partial and therapy failure and clinical deterioration have been described frequently in patients on infliximab or etanercept. A beneficial effect of human monoclonal anti-TNFα antibody adalimumab was seen in a small number of MKD patients.

- Most MKD patients are benefited by anti-IL-1 therapy. However, anti-IL-1-resistant disease may also occur. Example. tocilizumab (a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor). This drug is used when the patients are unresponsive towards Anakinra. (Shendi et al. treated a young woman in whom anakinra was ineffective with tocilizumab). It was found that it was effective in reducing the biochemical and clinical inflammation [30].Stoffels et al. observed reduction of frequency and severity of the inflammatory attacks, although after several months of treatment one of these two patients persistently showed mild inflammatory symptoms in the absence of biochemical inflammatory markers.

- A beneficial effect of hematopoietic stem cell transplantation can be used in severe mevalonate kinase deficiency conditions (Improvement of cerebral myelinisation on MRI after allogenic stem cell transplantation was observed in one girl). But, liver transplantation did not influence febrile attacks in this patient.

Because LAL deficiency is inherited, each sibling of an affected individual has a 25% chance of having pathological mutations in LAL genes from both their mother and their father, a 50% chance of having a pathological mutation in only one gene, and a 25% chance of having no pathological mutations. Genetic testing for family members and genetic prenatal diagnosis of pregnancies for women who are at increased risk are possible if family members carrying pathological mutations have been identified.

Typically, diagnosis involves several preliminary tests of immune function, including basic evaluation of the humoral immune system and the cell-mediated immune system. A WBC differential will reveal extremely elevated levels of neutrophils (on the order of 6-10x normal) because they are unable to leave the blood vessels.

In the case of LAD-I, specific diagnosis is done by flow cytometry. This technique will reveal absent or reduced CD18 expression in the leukocyte membrane. Recently, prenatal diagnosis systems has been established, allowing an early detection of the disease.

LAD-II diagnosis includes the study of different glycosilated forms of the transferrin protein. In LAD-III, as platelet function is also affected, this could be used to differentiate it from the other types.

Blood tests are neede to differentiate FVII deficiency from other bleeding disorders. Typical is a discordance between the prolonged prothrombin time (PT) and normal levels for the activated partial thromboplastin time (APTT). FVII levels are <10IU/dl in homozygous individuals, and between 20-60 in heterozygous carriers. The FCVII: C assay supports the diagnosis.

The FVII gene (F7) is found on chromosome 13q34. Heterogeneous mutations have been described in FVII deficient patients.

In most regions, galactosemia is diagnosed as a result of newborn screening, most commonly by determining the concentration of galactose in a dried blood spot. Some regions will perform a second-tier test of GALT enzyme activity on samples with elevated galactose, while others perform both GALT and galactose measurements. While awaiting confirmatory testing for classic galactosemia, the infant is typically fed a soy-based formula, as human and cow milk contains galactose as a component of lactose. Confirmatory testing would include measurement of enzyme activity in red blood cells, determination of Gal-1-P levels in the blood, and mutation testing. The differential diagnosis for elevated galactose concentrations in blood on a newborn screening result can include other disorders of galactose metabolism, including galactokinase deficiency and galactose epimerase deficiency. Enzyme assays are commonly done using fluorometric detection or older radioactively labeled substrates.

The condition is diagnosed by blood tests in the laboratory when it is noted that special blood clotting test are abnormal. Specifically prothrombin time (PT) or activated partial thromboplastin time(aPTT) are prolonged. The diagnosis is confirmed by an assay detecting very low or absent FXII levels.

The FXII (F12) gene is found on chromosome 5q33-qter.

In hereditary angioedema type III an increased activity of factor XII has been described.

In individuals with marked hyperammonemia, a urea cycle disorder is usually high on the list of possible causes. While the immediate focus is lowering the patient's ammonia concentrations, identifying the specific cause of increased ammonia levels is key as well.

Diagnostic testing for OTC deficiency, or any individual with hyperammonemia involves plasma and urine amino acid analysis, urine organic acid analysis (to identify the presence or absence of orotic acid, as well as rule out an organic acidemia) and plasma acylcarnitines (will be normal in OTC deficiency, but can identify some other causes of hyperammonemia). An individual with untreated OTC deficiency will show decreased citrulline and arginine concentrations (because the enzyme block is proximal to these intermediates) and increased orotic acid. The increased orotic acid concentrations result from the buildup of carbamoyl phosphate. This biochemical phenotype (increased ammonia, low citrulline and increased orotic acid) is classic for OTC deficiency, but can also be seen in neonatal presentations of ornithine aminotransferase deficiency. Only severely affected males consistently demonstrate this classic biochemical phenotype.

Heterozygous females can be difficult to diagnose. With the rise of sequencing techniques, molecular testing has become preferred, particularly when the disease causing mutations in the family are known. Historically, heterozygous females were often diagnosed using an allopurinol challenge. In a female with reduced enzyme activity, an oral dose of allopurinol would be metabolized to oxypurinol ribonucleotide, which blocks the pyrimidine biosynthetic pathway. When this induced enzymatic block is combined with reduced physiologic enzyme activity as seen in heterozygotes, the elevation of orotic acid could be used to differentiate heterozygotes from unaffected individuals. This test was not universally effective, as it had both false negative and false positive results.

Ornithine transcarbamylase is only expressed in the liver, thus performing an enzyme assay to confirm the diagnosis requires a liver biopsy. Before molecular genetic testing was commonly available, this was one of the only methods for confirmation of a suspected diagnosis. In cases where prenatal diagnosis was requested, a fetal liver biopsy used to be required to confirm if a fetus was affected. Modern molecular techniques have eliminated this need, and gene sequencing is now the preferred method of diagnosis in asymptomatic family members after the diagnosis has been confirmed in a proband.

The activity of arylsulfatase E can be measured with the substrate 4-methylumbelliferyl sulfate.

In the world less than 1 in 1.00.000 have HIDS [5]. 200 individuals throughout the world do suffer from MVK.

CDPX1 activity may be inhibited by warfarin because it is believed that ARSE has enzymatic activity in a vitamin K producing biochemical pathway. Vitamin K is also needed for controlling binding of calcium to bone and other tissues within the body.

There are several treatments available for factor VII deficiency; they all replace deficient FVII.

1. Recombinant FVIIa concentrate (rFVIIa) is a recombinant treatment that is highly effective and has no risk of fluid overload or viral disease. It may be the optimal therapy.

2. Plasma derived Factor VII concentrate (pdFVII) : This treatment is suitable for surgery but can lead to thrombosis. It is virus attenuated.

3. Prothrombin complex concentrate (PCC) containing factor VII: this treatment is suitable for surgery, but has a risk of thrombosis. It is virus attenuated.

4. Fresh frozen plasma (FFP): This is relatively inexpensive and readily available. While effective this treatment carries a risk of blood-borne viruses and fluid overload.

In congenital FXII deficiency treatment is not necessary. In acquired FXII deficiency the underlying problem needs to be addressed.

There are 2 forms of epimerase deficiency: benign RBC deficiency and Severe liver deficiency. Severe form is similar to galactosemia.

The condition can be prevented by using chloramphenicol at the recommended doses and monitoring blood levels, or alternatively, third generation cephalosporins can be effectively substituted for the drug, without the associated toxicity.

Medical Care

- Treatment may be provided on an outpatient basis.

- Cataracts that do not regress or disappear with therapy may require hospitalization for surgical removal.

Surgical Care

- Cataracts may require surgical removal.

Consultations

- Biochemical geneticist

- Nutritionist

- Ophthalmologist

Diet

- Diet is the foundation of therapy. Elimination of lactose and galactose sources suffices for definitive therapy.

Activity

- No restriction is necessary.

(Roth MD, Karl S. 2009)