Diagnosis of TNDM and PNDM

The diagnostic evaluations are based upon current literature and research available on NDM. The following evaluation factors are: patients with TNDM are more likely to have intrauterine growth retardation and less likely to develop ketoacidosis than patients with PNDM. TNDM patients are younger at the age of diagnosis of diabetes and have lower insulin requirements, an overlap occurs between the two groups, therefore TNDM cannot be distinguished from PNDM based clinical feature. An early onset of diabetes mellitus is unrelated to autoimmunity in most cases, relapse of diabetes is common with TNDM, and extensive follow ups are important. In addition, molecular analysis of chromosomes 6 defects, KCNJ11 and ABCC8 genes (encoding Kir6.2 and SUR1) provide a way to identify PNDM in the infant stages. Approximately,50% of PNDM are associated with the potassium channel defects which are essential consequences when changing patients from insulin therapy to sulfonylureas.

TNDM Diagnosis associated with Chromosome 6q24 Mutations

The uniparental disomy of the chromosome can be used as diagnostic method provide proof by the analysis of polymorphic markers is present on Chromosome 6. Meiotic segregation of the chromosome can be distinguished by comparing allele profiles of polymorphic makers in the child to the child's parents' genome. Normally, a total uniparental disomy of the chromosome 6 is evidenced, but partial one can be identified. Therefore, genetic markers that are close to the region of interest in chromosome 6q24 can be selected. Chromosome duplication can found by that technique also.

Medical Professionals of NDM

- Physician

- Endocrinologist

- Geneticist Counselor

Diagnostic Test of NDM

- "Fasting plasma glucose test": measures an diabetic's blood glucose after he or she has gone 8 hours without eat. This test is used to detect diabetes or pre-diabetes

- "Oral glucose tolerance test"- measures an individual's blood glucose after he or she have gone at least 8 hours without eating and two hours after the diabetic individual have drunk a glucose-containing beverage. This test can be used to diagnose diabetes or pre-diabetes

- "Random plasma glucose test"-the doctor checks one's blood glucose without regard to when an individual may have ate his or her last meal. This test, along with an evaluation of symptoms, are used to diagnose diabetes but not pre-diabetes.

Genetic Testing of NDM

- "Uniparental Disomy Test:"

Samples from fetus or child and both parents are needed for analysis. Chromosome of interest must be specified on request form. For prenatal samples (only): if the amniotic fluid (non-confluent culture cells) are provided. Amniotic fluid is added and charged separately. Also, if chorionic villus sample is provided, a genetic test will be added and charged separately. Microsatellites markers and polymerase chain reaction are used on the chromosomes of interest to test the DNA of the parent and child to identify the presence of uni"parental disomy""."

- Intrauterine Growth Restriction

"Apgar score is" a test given after birth to test the baby's physical condition and evaluate if special medical care is needed.

Causes of NDM

PNDM and TNDM are inherited genetically from the mother or father of the infant. Different genetic inheritance or genetic mutations can lead to different diagnosis of NDM (Permanent or Transient Neonatal Diabetes Mellitus). The following are different types of inheritance or mutations:

- "Autosomal Dominant": Every cell has two copies of each gene-one gen coming from the mother and one coming from the father. Autosomal dominant inheritance pattern is defined as a mutation that occurs in only one copy of the gene. A parent with the mutation can pass on a copy of the gene and a parent with the mutation can pass on a copy of their working gene (or a copy of their damaged gene). In an autosomal dominant inheritance, a child who has a parent with the mutation has a 50% possibility of inheriting the mutation.

- "Autosomal Recessive" -Autosomal recessive-Generally, every cells have two copies of each gene-one gene is inherited from the mother and one gene is inherited from the father. Autosomal recessive inheritance pattern is defined as a mutation present in both copies if the gene in order for a person to be affected and each parent much pass on a mutated gene for a child to be affected. However, if an infant or child has only one copy, he or she are a carrier of the mutation. If moth parents are carriers of the recessive gene mutation, each child have a 25% chance of inheriting the gene.

- "Spontaneous": A new mutation or change occurs within the gene.

- "X-linked:" When a trait or disease happens in a person who has inherited a mutated gene on the X chromosome (one of the sex chromosome).

Prevention: There are no current prevention methods, because TNDM or PNDM are inherited genetically.

Chronic hyperglycemia due to any cause can eventually cause blood vessel damage and the microvascular complications of diabetes. The principal treatment goals for people with MODY — keeping the blood sugars as close to normal as possible ("good glycemic control"), while minimizing other vascular risk factors — are the same for all known forms of diabetes.

The tools for management are similar for all forms of diabetes: blood testing, changes in diet, physical exercise, oral hypoglycemic agents, and insulin injections. In many cases these goals can be achieved more easily with MODY than with ordinary types 1 and 2 diabetes. Some people with MODY may require insulin injections to achieve the same glycemic control that another person may attain with careful eating or an oral medication.

When oral hypoglycemic agents are used in MODY, the sulfonylureas remain the oral medication of first resort. When compared to patients with type 2 diabetes, MODY patients are often more sensitive to sulphonylureas, such that a lower dose should be used to initiate treatment to avoid hypoglycaemia. Patients with MODY less often suffer from obesity and insulin resistance than those with ordinary type 2 diabetes (for whom insulin sensitizers like metformin or the thiazolidinediones are often preferred over the sulfonylureas).

Currently, MODY is the final diagnosis in 1%–2% of people initially diagnosed with diabetes. The prevalence is 70–110 per million population. 50% of first-degree relatives will inherit the same mutation, giving them a greater than 95% lifetime risk of developing MODY themselves. For this reason, correct diagnosis of this condition is important. Typically patients present with a strong family history of diabetes (any type) and the onset of symptoms is in the second to fifth decade.

There are two general types of clinical presentation.

- Some forms of MODY produce significant hyperglycemia and the typical signs and symptoms of diabetes: increased thirst and urination (polydipsia and polyuria).

- In contrast, many people with MODY have no signs or symptoms and are diagnosed either by accident, when a high glucose is discovered during testing for other reasons, or screening of relatives of a person discovered to have diabetes. Discovery of mild hyperglycemia during a routine glucose tolerance test for pregnancy is particularly characteristic.

MODY cases may make up as many as 5% of presumed type 1 and type 2 diabetes cases in a large clinic population. While the goals of diabetes management are the same no matter what type, there are two primary advantages of confirming a diagnosis of MODY.

- Insulin may not be necessary and it may be possible to switch a person from insulin injections to oral agents without loss of glycemic control.

- It may prompt screening of relatives and so help identify other cases in family members.

As it occurs infrequently, many cases of MODY are initially assumed to be more common forms of diabetes: type 1 if the patient is young and not overweight, type 2 if the patient is overweight, or gestational diabetes if the patient is pregnant. Standard diabetes treatments (insulin for type 1 and gestational diabetes, and oral hypoglycemic agents for type 2) are often initiated before the doctor suspects a more unusual form of diabetes.

Hyperglycerolemia is caused by excess glycerol in the bloodstream. People with more severe cases of glycerol kinase deficiency may have a deletion of the GK gene that is large enough to see by routine cytogenetic evaluation. It has been found an x-linked recessive inheritance pattern of the trait when a study was conducted on a grandfather and grandson. In addition, there is a high prevalence of [diabetes mellitus] in this family. There is no known prevention for hyperglycerolemia because it is caused by a mutation or deletion of an individual's genetic code.

According to Clinicaltrials.gov, there are no current studies on hyperglycerolemia.

Clinicaltrials.gov is a service of the U.S. National Institutes of Health. Recent research shows patients with high concentrations of blood triglycerides have an increased risk of coronary heart disease. Normally, a blood glycerol test is not ordered. The research was about a child having elevated levels of triglycerides when in fact the child had glycerol kinase deficiency. This condition is known as pseudo-hypertriglyceridemia, a falsely elevated condition of triglycerides. Another group treated patients with elevated concentrations of blood triglycerides with little or no effect on reducing the triglycerides. A few laboratories can test for high concentrations of glycerol, and some laboratories can compare a glycerol-blanked triglycerides assay with the routine non-blanked method. Both cases show how the human body may exhibit features suggestive of a medical disorder when in fact it is another medical condition causing the issue.

Initially, patients with neonatal or early-childhood onset diabetes are possible candidates for having Wolcott–Rallison syndrome. The other symptoms include the multiple epiphyseal dysplasia, osteopenia, intellectual disability, and hepatic and renal dysfunction. Patients with the symptoms that line up with Wolcott–Rallison syndrome can be suggested for genetics testing. The key way to test for this disease specifically is through genetic testing for the EIKF2AK3 mutation. Molecular genetic analysis can be done for the patient and the parents to test for de novo mutations or inherited. It can also show whether the patient's parents are heterozygotes or homozygotes for the normal phenotype. X-Rays can show bone age in relation to actual age. Typically the bond age is a few years less than the actual in the patients with WRS. Hypothyroidism is rare is WRS patients but can occur.

In order to be diagnosed with AGU an individual takes a urine test, which will show indication of an increased amount of aspartylglucosamin being secreted. The confirmation of the diagnosis of aspartylglucosaminuria requires a blood test. This helps show if the enzyme aspartylglucosaminidase is present or partially absent. A skin simple will also show the amount of aspartylglucosaminidase present.

When families have a child who has already been diagnosed with AGU, they have the option to observe the enzyme's activity that codes for AGU in future pregnancy, to help determine if the next child will also have a positive diagnosis for aspartylglucosaminuria.

The most common method to manage hypoglycemia and diabetes is with an insulin pump. . However in infants and very young children long acting insulins like Glargine and Levemir are preferred to prevent recurrent hypoglycemia . As soon as parent knows Walcott-Rallison syndrome is the source, treatment or therapy plans need to be drawn up along with frequent check ins to make sure kidney and liver functions are around normal and insulin therapy are working. If needed, the patient can undergo thyroxin therapy in order to maintain proper thyroid stimulating hormone levels. This has only been needed in a few cases were hypothyroidism was present in the patient.

Risk factors of early neonatal hypocalcemia

- Prematurity

- Perinatal asphyxia

- Diabetes mellitus in the mother

- Maternal hyperparathyroidism

- Intrauterine growth retardation (IUGR)

- Iatrogenic

Risk factors of late neonatal hypocalcemia

- Exogenous phosphate load

- Use of gentamicin

- Gender and ethnic: late neonatal hypocalcemia occurred more often in male infants and Hispanic infants

- Others

Once the diagnosis of polymicrogyria has been established in an individual, the following approach can be used for discussion of prognosis:

A pregnancy history should be sought, with particular regard to infections, trauma, multiple gestations, and other documented problems. Screening for the common congenital infections associated with polymicrogyria with standard TORCH testing may be appropriate. Other specific tests targeting individual neurometabolic disorders can be obtained if clinically suggested.

The following may help in determining a genetic etiology:

Family history

It is important to ask for the presence of neurologic problems in family members, including seizures, cognitive delay, motor impairment, pseudobulbar signs, and focal weakness because many affected family members, particularly those who are older, may not have had MRI performed, even if these problems came to medical attention. In addition, although most individuals with polymicrogyria do present with neurologic difficulties in infancy, childhood, or adulthood, those with mild forms may have no obvious deficit or only minor manifestations, such as a simple lisp or isolated learning disability. Therefore, if a familial polymicrogyria syndrome is suspected, it may be reasonable to perform MRI on relatives who are asymptomatic or have what appear to be minor findings. The presence of consanguinity in a child's parents may suggest an autosomal recessive familial polymicrogyria syndrome.

Physical examination

A general physical examination of the proband may identify associated craniofacial, musculoskeletal, or visceral malformations that could indicate a particular syndrome. Neurologic examination should assess cognitive and mental abilities, cranial nerve function, motor function, deep tendon reflexes, sensory function, coordination, and gait (if appropriate).

Genetic testing

Histidenemia is characterized by increased levels of histidine, histamine and imidazole in blood, urine and cerebrospinal fluid. This also results in decreased levels of the metabolite urocanic acid in blood, urine, and skin cells. In Japan, neonatal screening was previously performed on infants within 1 month of birth; infants demonstrating a blood histidine level of 6 mg/dl or more underwent careful testing as suspected histidinemia cases. A typical characteristic of histidinemia is an increase in the blood histidine levels from normal levels (70-120 μM) to an elevated level (290-1420 μM). Further testing includes: observing histidine as well as imidazolepyruvic acid metabolites in the urine. However, neonatal urine testing has been discontinued in most places, with the exception of Quebec.

Medical diagnosis is required. Clinical tests can be performed, as well as molecular genetic testing. The available tests include:

Sequence analysis of the entire coding region

- Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) - Sanger Sequencing: Diagnosis, Mutation Confirmation, Pre-symptomatic, Risk Assessment, Screening

- Craniosynostosis: Diagnosis

- Invitae FGFR3-Related Disorders Test: Pre-symptomatic, Diagnosis, Therapeutic management

Mutation scanning of select exons

- Skeletal Dysplasia Panel: Diagnosis, Prognostic

Sequence analysis of select exons

- Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN, FGFR3): Diagnosis, Mutation Confirmation, Risk Assessment

- Severe Achondroplasia, Developmental Delay, Acanthosis Nigricans: Diagnosis, Mutation Confirmation

Deletion/duplication analysis

- Invitae FGFR3-Related Disorders Test: Pre-symptomatic, Diagnosis, Therapeutic management

Life with SADDAN is manageable, although therapy, surgery, and lifelong doctor surveillance may be required.

Tests are either conducted at birth, or later in early childhood via: fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (aCGH), and EHMT1 sequencing.

FISH is a screening test that uses multicolour probes or comparative genomic hybridization to find any chromosome irregularities in a genome. It can be used for gene mapping, detecting aneuploidy, locating tumours etc. The multicolour probes attach to a certain DNA fragment. MLPA is a test that finds and records DNA copy change numbers through the use of PCR. MLPA can be used to detect tumours in the glial cells of the brain, as well as chromosomal abnormalities. Array-based comparative genomic hybridization (aCGH) tracks chromosome deletions and or amplifications using fluorescent dyes on genomic sequences of DNA samples. The DNA samples (which are 25-80 base pairs in length) are then placed on slides to be observed under microscope. Lastly, EHMT1 sequencing is a process in which a single-strand of DNA from the EHMT1 gene is removed, and DNA polymerase is added in order to synthesize complementary strands. In turn, this allows scientists to map out a person's DNA sequence allowing for a diagnosis to be made.

Parents of a proband

- The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.

- Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

- At conception, each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

- Once an at-risk sibling is known to be unaffected, the risk of his/her being a carrier is 2/3.

- Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

- Offspring of a proband are obligate heterozygotes and will therefore carry one mutant allele.

- In populations with a high rate of consanguinity, the offspring of a person with GPR56-related BFPP and a reproductive partner who is a carrier of GPR56-related BFPP have a 50% chance of inheriting two GPR56 disease-causing alleles and having BFPP and a 50% chance of being carriers.

Other family members of a proband.

- Each sibling of the proband's parents is at a 50% risk of being a carrier

It has been suggested that a possible method of treatment for histidinemia is through the adoption of a diet that is low in histidine intake. However, the requirement for such dietary restrictions is typically unnecessary for 99% of all cases of histidinemia.

The diagnosis of CTD is usually suspected based on the clinical presentation of mental retardation, abnormalities in cognitive and expressive speech, and developmental delay. Furthermore, a family history of X-linked intellectual disability, developmental coordination disorder, and seizures is strongly suggestive. Initial screening of CTD involves obtaining a urine sample and measuring the ratio of creatine to creatinine. If the ratio of creatine to creatinine is greater than 1.5, then the presence of CTD is highly likely. This is because a large ratio indicates a high amount of creatine in the urine. This, in turn, indicates inadequate transport of creatine into the brain and muscle. However, the urine screening test often fails in diagnosing heterozygous females. Studies have demonstrated that as a group heterozygous females have significantly decreased cerebral creatine concentration, but that individual heterozygous females often have normal creatine concentrations found in their urine. Therefore, urine screening tests are unreliable as a standard test for diagnosing CTD.

A more reliable and sophisticated manner of testing for cerebral creatine concentrations is through "in vivo" proton magnetic resonance spectroscopy (1H MRS). "In vivo" 1H MRS uses proton signals to determine the concentration of specific metabolites. This method of testing is more reliable because it provides a fairly accurate measurement of the amount of creatine inside the brain. Similar to urine testing, a drawback of using 1H MRS as a test for CTD is that the results of the test could be attributed to any of the cerebral creatine deficiencies. The most accurate and reliable method of testing for CTD is through DNA sequence analysis of the SLC6A8 gene. DNA analysis of SLC6A8 allows the identification of the location and type of mutation causing the cerebral creatine deficiency. Furthermore, DNA analysis of SLC6A8 is able to prove that a cerebral creatine deficiency is due to CTD and not GAMT or AGAT deficiency.

Plasma and cerebrospinal fluid levels of pipecolic acid are frequently elevated in patients with PDE, though it is a non-specific biomarker. α-aminodipic semialdehyde is elevated in urine and plasma and is a more specific biomarker for PDE. Improvements in these biomarkers have been reported with the implementation of a lysine-restricted diet. Initial studies evaluating the safety and efficacy of lysine restriction evaluated developmental and cognitive outcomes by age-appropriate tests and parental observations.

ONH is diagnosed by ophthalmoscopic examination. Patients with ONH exhibit an optic nerve that appears smaller than normal and different in appearance from small optic nerves caused by other eye conditions such as optic (nerve) atrophy.

DM:DD ratio has proven to be a clinically useful measurement to help diagnose optic nerve hypoplasia. Where "DM" represents the distance from Disk to Macula, and "DD" represents Disc Diameter.

The mean disc diameter (DD) is (Vertical diameter of Disc+Horizontal diameter of Disc)divided by 2. The distance between the center of the disc and the macula is DM.

"Interpretation:" When the ratio of DM to DD is greater than 3, ONH is suspected, and when it is greater than 4, Optic Nerve Hypoplasia is definite.

MDDS is diagnosed based on systemic symptoms presenting in infants, followed by a clinical examination and laboratory tests (for example, high lactate levels are common) medical imaging, and usually is finally confirmed and formally identified by genetic testing.

Most individuals with SBCADD are identified through newborn screening, where they present with an elevation of a five carbon acylcarnitine species. Confirmatory testing includes plasma and urine analysis to identify the carnitine and glycine conjugates of 2-methylbutyryl-CoA.

Due to its recent discovery, there are currently no existing treatments for Kleefstra syndrome.

Congenital lactic acidosis can be suspected based on blood or cerebrospinal fluid tests showing high levels of lactate; the underlying genetic mutation can only be diagnosed with genetic testing.

Neonatal hypocalcemia is an abnormal clinical and laboratory hypocalcemia condition that is frequently observed in infants.[1]

Healthy term infants go through a physiological nadir of serum calcium levels at 7.5 - 8.5 mg/dL by day 2 of life. Hypocalcemia is a low blood calcium level. A total serum calcium of less than 8 mg/dL (2mmol/L) or ionized calcium less than 1.2 mmol/L in term neonates is defined as hypocalcemia. In preterm infants, it is defined as less than 7mg/dL (1.75 mmol/L) total serum calcium or less than 4mg/dL (1 mmol/L) ionized calcium. [2]

Both early onset hypocalcemia (presents within 72h of birth) and late onset hypocalcemia (presents in 3-7 days after birth) require calcium supplementation treatment.