Transcript 4 Propionic Acidemia-201311261709x

Propionic Acidemia
Summary
Disease characteristics (I)
The spectrum of propionic acidemia (PA) ranges from neonatal-onset to late-onset
disease.
•
Neonatal-onset propionic acidemia (PA), the most common form, is characterized by
poor feeding, vomiting, and somnolence in the first days of life in a previously healthy
infant, followed by lethargy, seizures, coma, and death. It is frequently accompanied
by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia,
and cytopenias.
•
Late-onset propionic acidemia (PA) includes developmental regression, chronic
vomiting, protein intolerance, failure to thrive, hypotonia, and occasionally basal
ganglia infarction (resulting in dystonia and choreoathetosis) and cardiomyopathy.
Affected children can have an acute decompensation that resembles the neonatal
presentation and is precipitated by a catabolic stress such as infection, injury, or
surgery.
•
Isolated cardiomyopathy and arrhythmia can be observed on rare occasion in the
absence of clinical metabolic decompensation or neurocognitive deficits.
Disease characteristics (II)
•
Manifestations of neonatal and late-onset propionic acidemia (PA) over time include:
– growth impairment,
– intellectual disability,
– seizures,
– basal ganglia lesions,
– pancreatitis,
– cardiomyopathy.
•
Other rarely reported complications include optic atrophy, hearing loss, premature
ovarian insufficiency (POI), and chronic renal failure.
Diagnosis/testing
•
propionic acidemia (PA) is caused by deficiency of propionyl-CoA carboxylase (PCC),
the enzyme that catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA.
•
Newborns with propionic acidemia (PA) tested by expanded newborn screening have
elevated C3 (propionylcarnitine).
•
Testing of urine organic acids in persons who are symptomatic or those detected by
newborn screening reveals elevated 3-hydroxypropionate and the presence of
methylcitrate, tiglylglycine, and propionylglycine, which are normally not observed in
the urine.
•
Testing of plasma amino acids reveals elevated glycine.
•
Confirmation of the diagnosis relies on detection of either deficient PCC enzymatic
activity or biallelic mutations in PCCA or PCCB.
Management
Treatment of manifestations
•
The treatment of persons with acutely decompensated PA is a medical emergency:
•
treat precipitating factors such as infection;
•
arrest catabolism by providing high calorie and fluid intake;
•
minimize protein intake to reduce propiogenic precursors;
•
give intravenous carnitine;
•
correct hypoglycemia and metabolic acidosis;
•
care for the patient in a center with biochemical genetics expertise and the ability to
support urgent hemodialysis, especially if hyperammonemia is present.
Prevention of primary manifestations
•
Individualized dietary management to restrict propiogenic substrates; nasogastric or
gastrostomy feeding as needed; increased caloric intake during illness to prevent
catabolism; and continued multidisciplinary care with metabolic specialists.
•
Medications may include:
– L-carnitine supplementation;
– oral metronidazole to reduce propionate production by gut bacteria; and/or Ncarbamoylglutamate.
•
Orthotopic liver transplantation (OLT) may be indicated in those with frequent
metabolic decompensations, uncontrollable hyperammonemia, and/or restricted
growth.
Prevention of secondary complications
•
Consistent evaluation of the protein intake, depending on age, gender, severity of
disease and presence of other factors such as growth spurts, can avoid insufficient or
excessive protein restriction.
•
The latter can result in deficiency of essential amino acids and impaired growth, as
well as catabolism-induced metabolic decompensation.
Surveillance
•
Monitor closely patients with a catabolic stressor (fasting, fever, illness, injury, and
surgery) to prevent and/or detect and manage metabolic decompensations early.
•
Regularly assess:
(1) growth, nutritional status, feeding ability, psychomotor development;
(2) metabolic status by monitoring urine organic acids and plasma amino acids;
(3) renal function;
(4) complete blood count.
•
At intervals not yet determined, screen for: cardiomyopathy and arrhythmias; optic
atrophy; and premature ovarian insufficiency in females.
Diagnosis
Clinical Diagnosis
•
Neonatal-onset propionic acidemia (PA), the most frequently recognized form of
PA, manifests in the neonatal period as EITHER:
– An abnormal newborn screening (NBS): elevated propionylcarnitine (C3)
– OR
– Acute clinical deterioration of unexplained origin, in which an infant who appeared healthy at
birth develops nonspecific symptoms including vomiting, refusal to feed, and hypotonia in
the first few days of life. If untreated, encephalopathy, coma, seizures, and cardiorespiratory
failure can ensue.
•
Late-onset propionic acidemia PA includes developmental regression, chronic
vomiting, protein intolerance, failure to thrive, hypotonia, and movement disorders (i.e.
dystonia, choreoathetosis). These children can have an acute decompensation that
resembles the neonatal presentation and is precipitated by a catabolic stress such as
infection, injury, or surgery.
•
Isolated cardiomyopathy is a recently recognized presentation.
Testing (I)
•
PA is caused by deficiency of propionyl-CoA carboxylase (PCC), the mitochondrial
enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC
enzymatic activity deficiency results in accumulation of propionic acid and other
metabolites in plasma and urine.
•
Abnormalities frequently (but not universally) seen during acute decompensation
common to other organic acidemias:
◦ Mild to severe high-anion gap metabolic acidosis
◦ Elevated ketones in blood or urine (normally absent in healthy newborns)
◦ Low to normal blood glucose concentration
◦ Hyperammonemia (frequent)
◦ Neutropenia and occasionally thrombocytopenia
Testing (II)
Specialized biochemical evaluations for the diagnosis of propionic acidemia:
•
Urine organic acids:
– Elevated 3-hydroxypropionate (normal value: 3-10 mmol/mol Cr)
– Methylcitrate (normally absent)
– Tiglylglycine (normally absent)
– Propionylglycine (normally absent)
•
Occasionally lactate
•
Plasma amino acids:
– Elevated glycine
– Acylcarnitine profile: Elevated C3 (propionylcarnitine)
Metabolic pathway
Propionyl-CoA carboxylase (PCC) catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA, which
enters the Krebs cycle via succinyl-CoA.
Sources of propionate include: valine, isoleucine, threonine, methionine, odd-chain fatty acids, and cholesterol.
Deficiency of PCC results in propionic acidemia (PA) and accumulation of 3-OH propionate, methylcitrate and
glycine, among other metabolites. PCC is located inside the mitochondrion.
PCC, a heterododecamer (α6β6), comprises 6 α-subunits (orange) and six β-subunits (purple). Biotin (blue),
bicarbonate, and ATP have binding sites in the α-subunit.
The β-subunits form a central core.
Clinical Description
Natural History (I)
•
Neonatal onset. The typical presentation involves a healthy newborn who develops
poor feeding and decreased arousal in the first few days of life, followed by
progressive encephalopathy of unexplained origin. Unless diagnosed correctly and
managed promptly, neonates develop progressive encephalopathy, seizures, and
coma that result in death.
•
Late onset. The onset of symptoms in propionic acidemia (PA) varies depending on
several factors including residual enzymatic activity, the intake of propiogenic
precursors, and the occurrence of catabolic stressors.
•
Isolated cardiomyopathy in the absence of clinical metabolic decompensation or
neurocognitive deficits has been reported on rare occasion [Lee et al 2009].
Clinical Phenotypes
Onset
Neonatal onset
Clinical features
Findings
Poor feeding
Vomiting
Irritability
Lethargy
Progressive encephalopathy
Seizures
Coma
Respiratory failure
High anion-gap metabolic
acidosis
Ketonuria
Hyperammonemia (~80%)
Hypoglycemia
Elevated 3-OH propionic acid and
methylcitric acid
Hyperglycinemia
Elevated propionylcarnitine
Neutropenia
Thrombocytopenia
Acute, intermittent:
Encephalopathy, coma, and/or seizures precipitated by
catabolic stressors (e.g., intercurrent illness, surgery)
Late onset
Chronic progressive:
Vomiting, protein intolerance, failure to thrive, hypotonia,
developmental regression, movement disorders
Isolated cardiomyopathy 1
1. Lee et al [2009]
2. Broomfield et al [2010]
+/- Metabolic acidosis or
hyperammonemia
Elevated 3-OH propionic acid and
methylcitric acid
Hyperglycinemia
MRI abnormalities including basal
ganglia lesions 2
Natural History (II)
Early detection by newborn screening (NBS) and optimized management strategies offer
the potential to improve the survival and long-term outcome of individuals with propionic
acidemia (PA):
•
A study of 49 patients with PA treated at European centers showed a lower mortality
rate (~30%) in the first year of life than previously reported [Sass et al 2004].
•
A more recent study showed that although mortality was decreased in patients with
PA diagnosed through NBS, their neurologic outcome did not improve [Grünert et al
2012]. In this study, 63% of those detected through NBS were symptomatic at the time
of diagnosis.
Natural History (III) Metabolic decompensations
•
Children with propionic acidemia (PA) can
decompensations, especially in the first years of life.
•
Acidosis, hyperammonemia, pancreatitis, metabolic stroke, cardiomyopathy, bone
marrow suppression, seizures, and encephalopathy can accompany acutely deranged
metabolism.
•
These episodes, which typically require hospitalization and can be life threatening, are
usually precipitated by illnesses, infections, surgery, or any stress augmenting
catabolism.
•
The long-term cognitive outcome of individuals with propionic acidemia (PA) is
negatively correlated to the number of metabolic decompensations. Therefore,
metabolic decompensations should be recognized and treated promptly.
•
Of note, normal cognitive development has been described in several individuals with
late-onset (mild) forms of propionic acidemia (PA).
develop
episodic
metabolic
Natural History (III) Growth impairment
• Growth impairment may become evident with age.
• Failure to thrive may be exacerbated by malnutrition
secondary to poor feeding and excessive protein
restriction
Natural History (IV) Neurologic Manifestations
•
Neurologic manifestations include hypotonia, developmental regression,
neurocognitive deficits, stroke-like episodes, seizures, and movement disorders.
•
Seizures are frequent in early-onset PA and include tonic-clonic, myoclonic, focal, or
absence seizures. EEG abnormalities may precede the onset of seizures.
•
Individuals with PA are predisposed to basal ganglia lesions, especially during
episodes of acute encephalopathy or metabolic instability.
•
Basal ganglia infarction may be preceded by an acute “stroke-like” episode and
manifest as altered mental status, dystonia, choreoathetosis, and/or hemiplegia.
•
Brain MRI shows delayed myelination, symmetric basal ganglia disease, and cerebral
atrophy.
Natural History (V) Cardiomyopathy
•
Cardiomyopathy has recently been recognized as a common complication of propionic
acidemia (PA). Romano et al [2010] reported cardiomyopathy in six of 26 children from
a retrospective study; mean age of detection was age seven years. The age of
diagnosis of PA, amount of metabolic control, or amount of residual enzymatic activity
do not seem to modify the risk for cardiomyopathy.
•
Most individuals with cardiomyopathy have mild to moderate forms of PA that are well
controlled. Cardiomyopathy may resolve or progress to cardiac failure and has been
associated with sudden death in a child with PA
•
Cardiac rhythm abnormalities include prolonged QTc interval associated with syncope
and cardiac arrest .
Natural History (VI) Other complications
Pancreatitis, a well-known complication of PA and other organic acidemias, may be
recurrent and should be suspected in those with anorexia, nausea, and/or abdominal
pain.
Hematologic abnormalities. Neutropenia, thrombocytopenia, and rarely pancytopenia
are seen during acute decompensations. Affected persons are predisposed to infections.
Myelodysplasia has also been reported [Sipahi et al 2004].
Dermatologic manifestations resembling acrodermatitis enteropathica are frequently
associated with deficiency of essential amino acids, particularly isoleucine, which is
excessively restricted in the diet of persons with PA [Domínguez-Cruz et al 2011].
Other rare complications:
• Optic atrophy with acute visual loss [Williams et al 2009]
• Hearing loss
• Premature ovarian insufficiency (POI), described in some long-term survivors
• Chronic renal failure
Genotype-Phenotype Correlations
•
In general:
– Null alleles (PCCA: p.Arg313X, p.Ser562X; PCCB: p.Gly94X and several small
deletions/insertions and splicing mutations) are associated with a more severe form of PA;
– Missense mutations, in which partial enzymatic activity is retained (PCCA: p.Ala138Thr,
p.Ile164Thr, p.Arg288Gly; PCCB: p.Asn536Asp), are associated with a milder phenotype.
Exceptions include, for example, the three PCCB missense mutations p.Gly112Asp,
p.Arg512Cys, and p.Leu519Pro, which affect heterododecamer formation and are
associated with undetectable PCC enzyme activity and the severe phenotype.
•
Other PCCB mutations such as p.Glu168Lys result in a wide variety of clinical
manifestations among affected individuals.
•
The PCCB mutation p.Tyr435Cys has been identified in asymptomatic children through
newborn screening in Japan.
Incidence/Prevalence
•
The worldwide incidence of PA is estimated at 1:50,000 to 1:100,000.
•
The incidence is much higher in certain populations:
– Among the Inuit in Greenland the frequency at birth is 1:1000.
– In Saudi Arabia an incidence of 1:2000 to 1:5000 births has been reported.
One Hundred Eighty-two Cases with Organic
Acidurias Detected from 9566 High-risk Patients
Diseases
No.
%
Methylmalonic aciduria
116
63.7
Propionic aciduria
16
8.8
Multiple carboxylase deficiency
15
8.2
Glutaric aciduria type 2
11
6.0
Glutaric aciduria type 1
7
3.8
Maple syrup urine disease
5
2.7
Oxoprolinemia
3
1.6
Ketothiolase deficiency
3
1.6
Isovaleric aciduria
3
1.6
Methylcrotonyl CoA carboxylase deficiency
2
1.1
Alcaptonuria
1
0.5
Yang, Ann Acad Med Singapore 2008;37(Suppl 3):120-2
Differential Diagnosis
Elevated C3 on newborn screening (NBS) can be caused by methylmalonic acidemias (resulting
from methylmalonyl-CoA mutase deficiency, intracellular cobalamin metabolism) and severe
maternal B12 deficiency.
The differential diagnosis of propionic acidemia (PA) as suspected by the elevation of 3hydroxypropionate and methylcitrate on urine organic acids includes the following:
•
Biotin disorders, which also show elevation of 3-hydroxyvalerate and 3-methyl-crotonylglycine.
Biotinidase and holocarboxylase synthetase activities differentiate between biotinidase
deficiency and multiple carboxylase deficiency.
•
Methylmalonic acidemias, which have elevations of 2-methylcitric acid and 3-hydroxypropionate,
and additionally show massive elevations of methylmalonic acid
•
3-hydroxyisobutyric aciduria, which also has elevation of 3-hydroxyisobutyric acid
•
Bacterial contamination (including Propionibacterium)
Differential Diagnosis
Propionic acidemia should also be included in the differential diagnosis of many common pediatric
conditions:
•
Increased anion-gap metabolic acidosis. Possible causes are numerous and may include the
following:
•
Those conditions included in the commonly used mnemonic MUDPILES: methanol, uremia
(chronic renal failure), diabetic ketoacidosis, propylene glycol, infection, iron, isoniazid, lactic
acidosis, ethylene glycol, salicylates
•
Organic acidemias
Differential Diagnosis
•
Neonatal “sepsis” of unclear etiology in the newborn period should always prompt a
metabolic evaluation.
•
Pyloric stenosis. Infants with PA or other organic acidemias presenting with vomiting
and refusal to feed may be given the diagnosis of pyloric stenosis which may lead to
unnecessary surgery that provokes acute metabolic decompensation. Blood gas
analysis of infants with pyloric stenosis usually shows hypochloremic alkalosis.
•
Failure to thrive or recurrent vomiting of unclear etiology may be the only manifestation
of PA and other inborn errors of metabolism.
Differential Diagnosis
•
Child abuse or intoxication. PA should always be considered in the differential
diagnosis of intoxications. In at least one individual with an organic acidemia the
laboratory misidentified propionic acid as ethylene glycol.
•
Diabetic ketoacidosis. Persons with propionic acidemia (PA) usually have
ketoacidosis associated with hypoglycemia; however, hyperglycemia has also been
reported and confused initially with diabetic ketoacidosis.
•
Cardiomyopathy. An evaluation for propionic acidemia (PA) and other inborn errors
of metabolism is warranted in the evaluation of children with cardiomyopathy of
unknown origin.
Management
•
The management of patients with propionic acidemia (PA) is ideally performed at a
center with expertise in inborn errors of metabolism. The metabolic team comprises a
metabolic physician, nutritionist, and genetic counselor.
Evaluations Following Initial Diagnosis (I)
To establish the extent of disease and needs of an individual diagnosed with PA the
following evaluations are recommended :
•
Serial metabolic evaluations of blood gases, electrolytes, glucose, serum ammonia
concentration; plasma amino acids, carnitine and acylcarnitines; urine ketones and
urine organic acids to guide acute management until the patient stabilizes
•
Complete blood count to evaluate for cytopenias
•
Molecular genetic testing of PCCA and PCCB if not previously performed to aid in
genetic counseling and prediction of disease severity
Evaluations Following Initial Diagnosis (II)
Once the patient becomes stable, evaluations may include:
•
Clinical assessment of growth parameters, ability to feed, developmental status, and
neurologic status
•
Laboratory assessment of nutritional status (electrolytes, albumin, prealbumin, plasma
amino acids, vitamin levels [including thiamine and 25-hydroxyvitamin D], and trace
minerals) and renal function; complete blood count to monitor for cytopenias.
•
ECG and echocardiogram
•
EEG and brain MRI in symptomatic individuals
•
Age-appropriate developmental evaluation
•
Eye examination
•
Hearing evaluation
Treatment of Manifestations
Neonatal/Acute Decompensation
•
Injuries, illness, infections, birth, surgery, other forms of stress and hormonal changes
can produce a catabolic response that leads, among other things, to protein
breakdown with massive release of amino acids which may include propiogenic
precursors that cannot be metabolized in PA. The stress response may be
perpetuated by release of hormones. The goal of the acute management of persons
with decompensated PA is to reverse this process and to remove accumulated toxins.
•
The treatment of persons with acutely decompensated PA is a medical emergency
and requires care in a center with biochemical genetics expertise and the ability to
support urgent hemodialysis, especially if hyperammonemia is present.
Inpatient Management (I)
•
Manage ventilation and circulation as necessary.
•
Treat precipitating factors (fever, infection, dehydration, pain, vomiting, and other
sources of stress).
•
Aggressively stop catabolism by giving fluids and calories approximately 1.5 times
above the estimated baseline requirement in a glucose infusion rate of 10 mg/kg/min,
and more than 40% of calories with a parenteral lipid suspension. The use of anabolic
hormones (i.e., intravenous insulin drip) that may be needed to stop catabolism is
preferably undertaken in an intensive care setting.
•
Restrict intake of propiogenic precursors by avoidance of protein transiently (< 24-36
hours), or ideally, by the use of propiogenic-free parenteral amino acids, if available.
Transition to enteral feedings as soon as they are tolerated.
Inpatient Management (II)
Detoxify to reduce hyperammonemia.
•
Carnitine supplementation (100 mg/kg/day IV) may increase the detoxification of
propionic acid by conjugating into propionylcarnitine, which is excreted by the kidneys.
Alternatively, it may relieve intracellular coenzyme A accretion and provide a benefit
through this mechanism.
Inpatient Management (III)
Detoxify to reduce hyperammonemia.
•
Pharmacologic detoxification:
– Scavenger medications, such as those used in urea cycle disorders to help control
ammonia levels during acute decompensations, should be used with caution in the
treatment of hyperammonemia associated with PA as they lower glutamine levels, which
may in turn contribute to hyperammonemia. Scavenger medications include intravenous
sodium benzoate (250 mg/kg) and sodium phenylacetate (250 mg/kg) alone or in
combination (Ammunol®), L-Carnitine (Carnitene®),
– Oral N-carbamoylglutamate (carglumic acid; 100-250 mg/kg) has also been reported to aid
in the detoxification of ammonia during neonatal and acute decompensations [Filippi et al
2010, Schwahn et al 2010], L-Carnitine (Carnitene®).
•
Extracorporeal detoxification (hemodialysis or extracorporeal membrane oxygenation
[ECMO]) is frequently required in the acute infantile presentation of PA to control
severe metabolic acidosis and/or hyperammonemia. Peritoneal dialysis is not
recommended in this setting.
Home Management of Metabolic Status
The detection and management of metabolic decompensations at home are a critical part
of the chronic management of PA. Strategies to achieve home management should be
tailored for the conditions of each patient and family and may include the following:
•
At-home detection and monitoring of ketones
•
Use of anti-emetics such as ondansetron
•
Close monitoring of clinical status
•
Control of fluid-balance status
•
Modification of the diet under the direction of the metabolic team
Other
•
Any injury, illness, hospitalization, or surgical procedure should involve consultation
with the metabolic team.
•
The diagnosis and management of pancreatitis is the same as for pancreatitis of
other causes.
•
Neutropenia and other cytopenias usually improve with metabolic control of PA.
•
The management of cardiomyopathy and arrhythmias is similar to that from other
causes.
•
Dermatologic manifestations are usually secondary to nutritional deficiencies of
essential amino acids; these should be corrected.
•
The management of chronic renal failure does not differ from that for other causes of
renal failure; renal transplantation may be required.
Prevention of Primary Manifestations
•
The long-term management of propionic acidemia PA includes the following:
•
Individualized dietary management in order to restrict propiogenic substrates (valine,
methionine, isoleucine, threonine, and odd chain fatty acids), while ensuring normal
protein synthesis and preventing protein catabolism, amino acid deficiencies, and
growth restriction
•
Avoiding fasting and increasing calorie intake during illness to prevent catabolism
•
Metabolic monitoring (see Surveillance)
•
Supportive feeding (nasogastric or gastrostomy) as needed
•
Ongoing multidisciplinary care, including caregiver teaching and emergency bracelet
Prevention of Primary Manifestations
•
Medications including:
– L-carnitine supplementation at a dose of 50-100 mg/kg/day
– Intermittent oral metronidazole at a dose of 10-20 mg/kg/day to reduce propionate
production by gut bacteria
– N-carbamoylglutamate. However, its chronic use in PA needs to be further studied.
– Antiepileptic drugs, as needed
– Therapy of arrhythmias, as needed
Prevention of Primary Manifestations
•
Management before, during, and after any surgery by a metabolic team to ensure
adequate hydration and caloric intake in order to minimize the risk of
decompensations
•
Orthotopic liver transplantation (OLT). May be indicated in those with frequent
metabolic decompensations, uncontrollable hyperammonemia, and restricted growth.
Reported benefits of OLT include decrease in the frequency of metabolic
decompensations, improved quality of life, and reversal of dilated cardiomyopathy.
Liver transplantation has been performed successfully from unrelated donors and
from heterozygous related donors.
•
Continuous hemofiltration, extracorporeal membrane oxygenation (ECMO), and left
ventricular assist devices have been used while waiting for OLT
Prevention of Secondary Complications
•
It is suggested that protein intake be regularly monitored by a biochemical geneticist
and a nutritionist to avoid insufficient or excessive protein restriction.
•
Many factors should be taken into account to guide protein restriction: age, gender,
severity of PA, nutritional status, and presence of other factors such as intercurrent
illness, surgery, or growth spurts.
•
The effects of excessive protein restriction can include impaired growth, essential
amino acid deficiencies, and catabolism-induced metabolic decompensation.
Surveillance (I)
•
Monitor closely patients with a catabolic stressor (fasting, fever, illness, injury, and
surgery) to prevent and/or detect and manage metabolic decompensations early.
•
The following evaluations are performed at different intervals depending on factors
including age, disease severity, and presence of catabolic stressors.
•
Clinical evaluation should include assessment of the following:
– Growth
– Nutritional status
– Feeding ability
– Developmental and neurocognitive progress, as age-appropriate
Surveillance (II)
Laboratory evaluation should include:
•
Metabolic studies: urine organic acids (if available, quantitative plasma methylcitric
and propionate are preferable), plasma amino acids, serum ammonia concentration,
and quantitative acylcarnitine profile;
•
Nutritional studies: electrolytes, albumin, prealbumin, plasma amino acids, vitamin
levels (including thiamine and 25-hydroxyvitamin D), and trace minerals;
•
Complete blood count to monitor for cytopenias;
•
Renal function tests;
•
Amylase and lipase as needed to evaluate for pancreatitis.
Surveillance (III)
Evaluations:
•
Screening for cardiomyopathy and arrhythmias by echocardiogram, ECG, and Holter
monitor. The ideal screening frequency has not been defined.
•
Brain MRI and/or EEG as clinically indicated
•
Ophthalmologic evaluations to assess optic nerve changes. Frequency has not been
determined.
•
Screening for premature ovarian insufficiency (POI) in females. Frequency and
recommended age to begin screening has not been determined.