NEUROLOGICAL MANIFESTATIONS IN SOME HEREDITARY METABOLIC DISEASES IN CHILDREN
Neurological manifestations in some hereditary metabolic diseases in children. Inherited metabolic diseases in children are the most complex problems to be dealt with in neuropadiatrics, althouth these are rare. The complexity arises from the clinical syndromes as well as the increasing multitude of identified biochemical defects. Specific defects can lead to a wide spectrum of clinical manifestations with onset at variable ages. Sophisticated biochemical and molecular assays are needed for a precise diagnosis in many cases. The methods of diagnosis depend on the child’s age. The basical examinations of metabolism include: analys of glucose, lactate, ammonia, amino acids in plasma and CSF, level assessment of uric acid. Cerebral MRI may suggest the diagnosis of mitochondrial cytopathy. Early diagnosis of congenital anormalities of metabolism allows to choose a proper treatment, thus child’s condition improvement.
ACTUALITY
Inherited metabolic disorders are rare as individual entities, but all taken toghether constitute a varied group of diseases known to occur in a number of over 700 diseases and syndromes. They are called “inborn errors of metabolism “, a term introduced by Archibald Garrod (1902-1908) [7, 6]. This group includes a sum of various diseases, consecutive deviations to the normal development of various metabolic processes in which are involved: amino acids, carbohydrates, lipids, pigments, minerals, vitamins. Inborn diseases have autosomal-recessive and x-linked recessive inheritance most frequently [11]. These are enzymopathies, produced either by the disorder of enzime-catalysts, or by the disorder of enzymes responsible for the transport of biological substances. Enzyme disorders lead to excessive accumulation of metabolites toxic for organism and / or insufficient production of substances needed for a proper metabolism.
According to the size of the faulty molecules the inherited metabolic diseases are classified as follows:
- Diseases of small molecules (these often have an acute onset in the perinatal period or in early infancy): amino acids, organic acids, simple sugars.
- Diseases of large molecules (progressive chronic degenerative processes in older infants and children): glycogen, glycoproteins, lipids, mucopolysaccharides [9].
According to the pathogenetic classification the inherited metabolic diseases are devided into:
- Disorders that cause poisoning-represent inborn errors of intermediary metabolism leading to acute or porgresive intoxication as a result of accumulation of toxic compounds, proximal to the metabolic block. These are: the group of inborn errors of amino acid catabolism (phenylketonuria, maple syrup disease, homocystinuria, tyrosinemia, etc..), most organic acidurias (methylmalonic, propionic, isovaleric), congenital urea cycle defects, infant intolerance (galactosemia, hereditary fructose), metal poisoning (Wilson, Menkes, hemochromatosis), porphyria.
- Disorders involving energy metabolism, in their turn divided into: mitochondrial energy defects and cytoplasmic energy defects, the last being less severe. Mitochondrial defects are generally more severe and incurable. These include: congenital lactic acidemia (defects in the enzymes that transport pyruvate, also pyruvate carboxylase, pyruvate dehydrogenase and Krebs cycle enzymes defects), mitochondrial respiratory chain abnormalities (impaired respiratory chain itself, abnormal mitochondrial transport enzymes or abnormal synthesis of Q-10 coenzyme), fatty acid oxidation defects and ketone body metabolism defects. Only the the Q-10 coenzyme defect is partially treated. Cytoplasmic energy defects include disorders of glycogen metabolism, also glycolysis, gluconeogenesis, hyperinsulinemia, impaired metabolism of creatinine (treatable) and inborn errors of pentozo-phosphate pathway (incurable).
- Abnormalities involving complex molecules (being disturbed the normal function of organelles): lysosomal storage abnormalities, peroxisomal disorders, processing and transport disorders(alpha-1-antitrypsin), congenital anomalies of glycosylation, inborn errors of cholesterol synthesis [4].
In economically developed countries prenatal diagnosis of many inherited metabolic diseases is possible by finding the primary enzyme defect in the fetal tissue, and emphasizing the accumulation of metabolites or macromolecular storage products in amniotic fluid or fetal cells.
Recent researche revealed that the diagnosis of inborn errors of metabolism is important for the following reasons:
- some (phenylketonuria) benefit from specific treatment and children with these disorders have increased chances of survival;
- late diagnosis leads to irreversible neurological sequelae;
- for parents and relatives diagnosis is necessary in applying for genetic counseling;
- birth of a sick child can be prevented by contraception.
Obviously, to solve the problem with the diagnosis of inborn metabolic disorders new scientific ways of approaching, and the application of contemporany methods of examination are required. It has been proved that advanced technologies of early survey of fetal DNA (at 10-week) tend to replace prenatal diagnosis of inborn errors of metabolism by amniocentesis.
Early recognition of neuro-metabolic diseases is important for preventing serious complications of the CNS and improve child disability.
OBJECTIVES
Neurological assessment of inherited metabolic diseases according to the literature and setting the parameters for determining a timely and correct diagnosis of the diseases in question.
MATERIALS AND METHODS
The investigated facts have been taken from the literature on inherited metabolic diseases involving the nervous system. A survey has been thoroughly established clinical features of hereditary metabolic abnormalities in children. Clinical, biochemical and imaging parameters were assessed for establishment of a proper diagnosis.
RESULTS AND DISCUSSION
According to the investigated data, some of the features of hereditary metabolic diseases are:
- metabolic abnormalities occur rarely;
- epileptic seizures are a common manifestation of metabolic disorders;
- sometimes crises fail after a certain diet with special supplements;
- in many cases, antiepileptic drug therapy is administered (APR), which mostly is inefficient [12]. As causes of delayed diagnosis were determined to be:
- detection of neuro-metabolic disorders is hindered by the delay in recognition of early common phenotypes;
the false belief that inborn metabolic diseases have particular clinical manifestations; - similarity with the clinical manifestations of other diseases like: sepsis, renal growth process, intrauterine growth retardation, recurrent vomiting;
- clinical manifestations resembling those of other diseases, what is necessary for a differential diagnosis: sepsis, renal growth process, intrauterine growth retardation, recurrent vomiting;
In order to establish the clinical diagnosis are essential next steps:
- a detailed medical history, the most important step in a suspected metabolic disorder. Family history is very informative;
- the presence of unexplained neurological disorders:
- mental retardation, cerebral palsy, seizures;
- loss of previously acquired skillls is suggestive for a progressive degeneration of the CNS;
- in case you suspect an inborn metabolic disease further investigations are needed [13];
The features of inherited metabolic diseases are:
- the younger is child, the less diverse are the symptoms (these are associated with systemic signs);
- the most common clinical manifestations of metabolic encephalopathy in newborn are: seizures, apnea, recurrent vomiting and food refusal;
- in infancy the following simptoms associate: delay in development, spasticity or hypotonia, autistic manifestations, abnormal eye movements and choreoathetosis.
- the following clinical simptoms are present during the school period: poor academic performance in school, loss of sight, disturbances of behavior.
In many cases the diagnosis is delayed and this happens for the following reasons:
- accumulation of small molecules (amino acids, organic acids, simple sugars) exerts toxic effects on the nervous system;
- clinical symptoms arise with the child’s growth;
- metabolic diseases have a chronic evolution;
- often the problem remains hidden (“dormant”). Another disease or stress disturb the precarious balance, facilitating the onset of clinical symptoms;
- the prognosis in chronic forms is bad, but better compared to earlier forms.
Clinical peculiarities of metabolic inherited diseases in newborn and children in the sucking period are as follows:
- the presence of seizures (myoclonic, infantile spasms);
- lethargy or irritability, stupor, coma;
- abnormalities of muscle tone (spasticity or hypotonia);
- archaic and osteotendinous reflexes abnormalities;
- abnormal involuntary movements;
- lack of eye contact [13].
Clinical peculiarities of inherited metabolic diseases in preschool and school children are:
- seizures and epilepsy (myoclonus);
- episodes of lethargy or irritability, stupor or coma;
- the presence of cerebral palsy: spastic diplegia, spastic quadriplegia;
- ataxia and abnormal involuntary movements;
- progressive mental deterioration, dementia;
- setback of development;
- sensory alteration [13, 5];
- neurological symptoms that are often associated are: extrapyramidal symptoms (dystonia, opistotonus, choreoathetosis), cerebellar symptoms (ataxia), microcephaly or macrocephaly, speech disorders, visual disturbances, abnormal movements, apraxia, nystagmus and optic atrophy, macular cherry-red spot, or retinal degeneration [13].
According to a previous study (years of research: 1997-2005; Principles of diagnosis of inherited metabolic diseases in children. In: Bulletin of perinatology.Chișinău, 2005, no. 3, p 57-60) that included a sample of 109 children suspected for hereditary metabolic abnormalities some changes in the behavior of children and the following clinical and biochemical manifestations were found (see Table 1)
According to this study the most frequent clinical signs (see Table 1), which allowed to suspect a metabolic disease in early childhood were: persistent or intermittent vomiting, especially in combination with changes in diet (70.64%)), developing mass and waist restraint(73.4%), neurological abnormalities (100%) expressed by: sensory alteration, seizures (78.9%), abnormal muscle tone, absence or early loss of archaic reflexes, functional abnormalities (73.4%) expressed by: hepatosplenomegaly, liver failure.
Metabolic acidosis was present in 76% of patients, abnormal sweat and sweaty feet urine smell or maple syrup smell -in 20.2%, being characteristic for isovaleric acidemia, leucinosis. Some children with metabolic diseases had hypoglycemia (35%), hyponatremic dehydration (30%). Other patients had neutropenia (58.7%), thrombocytopenia (52.3%) (eg. propionic and methylmalonic acidemia). Less common signs found in metabolic pathology were: diarrhea (69.7%), hypothermia (9%), abnormal hair (18.3%), cardiomegaly (15.6%), cataract (5.5%). Changes were revealed in the laboratory tests in children with suspected metabolic diseases: urea (33%), creatinine (30.3%) – by renal tubular dysfunction, hyperbiliru binemia (56%), plasma amino acid spectrum (67.9%).
Systemic signs of metabolic inherited deseases are: the smell of urine (mouse, sweaty feet etc.), intrauterine growth retardation, growth failure (“failure to thrive”), refusing sucking and repeated vomiting, weak cry, cardiomyopathy, hepatomegaly or hepatosplenomegaly, fatty liver, fibrosis / cirrhosis, renal tubular degeneration, increased susceptibility to infections, bone marrow depression (neutropenia, thrombocyto penia, pancytopenia), seborrhea, alopecia or abnormal hairpili torti or trichorrhexisnodoza [13].
Biological routine tests when metabolic inborn disorders are suspected:
Blood examination (screening tests are very useful): CBC (complete blood count), glucose, calcium, blood gases, electrolytes (anion gap), ammonia (amoniemia), aminotransferases, lactic acid (blood lactate), pyruvic acid, uric acid, ketones (beta-OH-butyric and acidoacetic), vacuolated lymphocytes [5, 4].
Table 1. Clinical and biochemical abnormalities suggestive of metabolic disease
In the blood chemistry tests are suggestive the following parameters: ammonia (urea cycle abnormalities), lactate / pyruvate ratio (Leigh syndrome, other mitochondrial citopathies) amino acids, organic acids and other special metabolites, the ratio C26/C22 – very long chain fatty acids (adrenoleucodistrofia , Zellweger disease, the infantile type of Refsum disease). There are aslo studied fitanic acid, pipecolic acid, etc. [13, 5, 15].Leukocytes and erythrocytes in the peripheral blood are also examined:
- For erythrocytes: enzymatic tests for diagnosis of galactozemiei and porphyria are needed;
- For Leukocytes: lysosomal enzymes and other enzyme tests, genetic testing of DNA mutations, lipid and other inclusions (ceroid lipofuscinosis, gangliozidosis) are needed [5].
Examination of urine: pH, urinary ketones, sulfites, electrolytes, uric acid [5].
Routine metabolic screening: amino acids, organic acids and ferric chloride, galactose and other carbohydrates and mucopolysaccharides, sialic oligosaccharides, N-Acetylaspartic acid, excretion of copper and porphyrins, metachromatic oxalate granules, cystine crystals, reducing substances, DPNH (reduced diphosphopyridine nucleotide), nitroprusside, CTAB (Cetyl trimethylammonium bromide) or Berry stain, urine odor [15, 4].
Specific smell of urine can be suspected in the following pathologies:
- sweaty feet odor (glutaric acidemia type II and isoveleric acidemia);
- burnt sugar, caramel, maple syrup odor (maple syrup urine disease/MSUD or leucinosis);
- cabbage odor, sweet urine (methionine malabsorption);
- cat urine (multiple carboxylase deficiency);
- mice urine odor (phenylketonuria);
- rancid butter urine odor, fish urine odor (tyrosinemia)[5]
Increased protein in CSF will be assumed in the following diseases: metachromatic leukodystrophy, Krabbe disease, infant Adrenoleukodystrophy, Zellweger disease (sometimes), Refsum disease, Cock ayne syndrome [15].
Lactate / pyruvate ratio in the CSF is highly informative for the diagnosis of mitochondrial cytopathy [15].
Electrodiagnosis is helpful in some cases:
- electromyography and nerve conduction velocity: in neuropathies, motor neuron diseases and muscles;
- ophthalmic examination (electroretinogram and visual evoked responses);
- otorhinolaryngologic examination – BAER (brainstem auditory evoked responses);
- electroencephalography (provides critical infor mation for the diagnosis);
- medical imaging exams (brain CT and MRI): diffuse “hypersignal” in the white matter (Adrenoleukodystrophy, Canavan disease, Alexander disease, Krabbe disease); tiger’s-eye pattern of the basal ganglia points; Hallervorden-Spatz disease, “hypersignal” of the gray basal nuclei; acute mito chondrial encephalopathy [4];
- the biopsy of skin, conjunctiva, liver, brain are needed when noninvasive tests are insufficient for diagnosis.
In children with undiagnosed disease, laboratory investigations are important screening tools. Their usage depends, in part, on accessibility and cost.
A metabolic disease is suspected when:
- the onset of disease occurs in neonatal or antenatal period;
- when there are paroxysmal neurological phenomena (drug resistance), occurring mainly in childhood;
- there is a progressive psychomotor retardation or predominantly motor;
- inexplicable static encephalopathy is present [10].
In order to suspect one or another diagnosis the presence of neurological abnormalities is very conclusive. These may be:
- unexplained neurological disorders such as mental retardation, commonly found in children;
- seizures;
- cerebral palsy;
- loss of previously acquired ailities is suggestive for a progressive degeneration of the CNS and requires thorough investigation [5].
For the diagnosis of inherited metabolic diseases
are important the following points:
- the age at which first symptoms appear;
- identifying the main neurological and extraneurological signs displayed;
- the usage of simple additional tests.
Clinical manifestations of inherited metabolic diseases depend largely on:
- anatomical location of the pathological process (gray or white matter);
- predominant clinical symptoms (“poisoning” or energy deficits);
- the presence of toxic metabolites (small molecules and large);
- neurological symptoms (acute and chronic progressive encephalopathy);
- “poisoning” and energy deficits (accumulation of toxic compounds proximal to the metabolic block) are caused by impaired production of energy or impared usage of energy, as a result of myocardial, liver, muscle or brain abnormalities, aorganic aciduria, aminoacidopathies, abnormal urea cycle, galactosemia, fructosemia, tyrosinemia, hoarding disorders of glycogen, congenital lactic acidosis, disorders of fatty acid oxidation, mitochondrial respiratory disorders, peroxisomal anomalies [4]. The inherited metabolic disease’s onset occurs in the following periods of life: neonatal, infancy (1 and 12mo nths), toddler period (1 and 4 years), reschool period (juvenile form), teenage years (5 and 15 years) [13, 4].
In the neonatal period
placental anasarca syndrome and ascitic-oedematous syndrome, hepatosplenomegaly, signs of dysmorphism, malformation syndromes ( consequences of the metabolic disorders occurred in embryogenesis ), agenesis of the corpus callosum associated with neuronal migration disorder and myelination disorder, cerebral calcification and necrosis are suggestive of a metabolic inborn disease.
Metabolic encephalopathy and cerebral malformations (with onset in the neonatal period): agenesis of the corpus callosum is the most frequently reported anomaly (associated to neuronal migration disorders and myelination disorder, cerebral calcifications); Zellweger disease (abnormal neuronal migration); peroxisomopathy type Zellweger (inferior olive dysplasia); pyruvate dehydrogenase deficiency (agenesis of the corpus callosum, periventricular and inferior olive heterotopy, cystic necrosis of the gray nuclei and white matter); pyruvate carboxylase deficiency (cystic necrosis of white matter, corpus callosum hypoplasia);
nonketotic hyperglycemia (agenesis of the corpus callosum, cortical dysplasia); glutaric aciduria type II (cortical dysplasia); sulfate oxidase deficiency (multicystic necrosis of white matter); Smith-Lemli-Opitz syndrome (cerebellar and brain hypoplasia); deficit of carnitin palmitoyl transferase II (cortical dysplasia) [4].
The differential diagnosis of metabolic encephalopathy and cerebral malformations in the newborn includes the following diseases:
- antenatal encephalopathy (ischemic or hemorrhagic);
- acute hypoxic ischemia during birth;
- intracerebral haemorrhage (premature);
- infectious or inflammatory neonatal pathology or congenital disorders of central nervous system;
- birth defects;
- severe trauma at birth [14].
For the diagnosis are also suggestive the following: disorders of consciousness, coma, hypotonia, respiratory and digestive disorders, epileptic seizures, addi tional tests (lumbar puncture, brain MRI).
In infancy (1 and 12 months) are more specific:
Gaucher disease and Niemann-Pick II (hypotonia associated with visceromegaly); Krabbe disease (pyramidal syndrome, abolished osteotendinous reflexes); Menkes disease; Alpers syndrome; biotinidase deficiency (severe myoclonic epilepsy).
In the early infancy three general categories of pacients can be identified according to presence / absence of neurological and extra-neurological features:
- Category 1: Disorders associated with extraneurological features (lysosomal disorders and respiratory chain disorders , Barth syndrome,d-2-hy-droxyglutaric aciduria (with atrioventricular block), Menkes disease, Sjögren-Larsson syndrome, biotinidase deficiency, cytochrome-b5-reductase deficiency, Criggler-Najjar syndrome, EPEMA syndrome-characterised by an orthostatic acrocyanosis, relapsing petechiae, pyramidal signs, mental retardation and recurrent attacks of lactic acidosis).
- Category 2: Disorders with specific or suggestive neurological signs (Pyridoxamine-phosphate oxidase deficiency, Lesch-Nyhan syndrome, a deficiency of cytochrome-b5 reductase, Criggler – Najjar syndrome, the early-onset form of GA type I, cerebral creatine deficiency, x-linked Pelizaeus – Merzbacher syndrome, cerebral folate deficiency, GM-2 gangliosidosis , Krabbe disease, GA type I, Leigh syndrome, Canavan disease, Alexander leukodystrophy , urea cycle defects (mostly OTC deficiency), late-onset MSUD, OAs, GA type I, CDG, respiratory chain disorders, classic homocystinuria, Angelman syndrome).
- Category 3: Disorders with nonspecific developmental delay ( cyclohydrolase deficiency, tyrosine- hydroxylase deficiency, and aromatic amino acid decarboxylase deficiency, blood-brain barrier glucose transporter (GLUT-1) defect , cerebral folate deficiency syndrome ) [4].
For infants more common are the following diseases:
hypoglycemia, GLUT-1 deficiency, deficiency of creatine, biotinidase deficiency, aminoacidopathies, organic acidemia,congenital disorders of glycosylation; pyridoxin dependency; infantile neuronal ceroid lipofuscinoses (NCL) [4].
For the preschool period are more common: late infantile neuronal ceroid lipofuscinoses (NCL type-2) mucopolysacharidosis and glycoproteinosis, mito chondrial disorders, Alpers disease, lysosomal abnormalities [4].
In the late Infancy to Early Childhood (1-5 Years) diagnosis becomes easier. Five general categories can be defined :
- Category 1: With visceral, craniovertebral, ocular, or other somatic abnormalities (mucopolysaccharidosis types I and II, mucolipidosis type III, mucolipidosis type IV, oligosaccharidosis, Austin disease, Niemann-Pick disease type C, Gaucher disease type III and lactosyl ceramidosis, Sanfilippo syndrome, peroxisomal disorders, Pyrroline-5-carboxylate-synthase deficiency).
- Category 2: With progressive paraplegia and spasticity (Schindler disease, arginase deficiency, Cbl-synthesis defects, HHH syndrome).
- Category 3: Unsteady gait and uncoordinated movements (when standing, walking, sitting, reaching for objects, speaking, and swallowing) due to either ataxia, peripheral neuropathy, abnormal movements or myoclonia (late-onset forms of GM-1 and GM-2 gangliosidosis, late infantile Krabbe disease, ataxia, telangiectasia and CDG , Alpers syndrome , creatine deficiency , CDG, GLUT I, PDH deficiency, LCHAD deficiency, l-2-hydroxyglutaric aciduria, 3-methyl- glutaconic aciduria, MMA and PA).
- Category 4: Predominant epilepsy and myoclonus (Santavuori-Hagberg disease (CLN1) and Jansky-Bielchowski disease, myoclonic-epilepsy ragged red fibre (MERRF) syndrome, Schindler disease)
- Category 5: Isolated developmental arrest or regression (Sanfilippo disease, Rett syndrome) [4]. For the school period are common: mitochondrial disorders, juvenile neuronal ceroid lipofuscinoses (NCL 3), progressive myoclonic epilepsy [4].
The main features of these are: predominantly psychomotor or motor regression, characteristic neurological symptoms, behaviour disorders.
There are described 6 neurological syndromes that refers to this period:
- Category 1: With predominant extrapyramidal signs (parkinsonian syndrome, dystonia, choreoathetosis).
- Category 2: With severe neurological and mental deterioration and diffuse central nervous system involvement (juvenile metachromatic leukodystrophy, X-linked adrenoleukodystrophy, Krabbe disease, juvenile GM-1 and GM-2 gangliosidoses or respiratory chain disorders. peroxisomal biogen esis defects, Niemann-Pick disease type C or Gaucher disease type III).
- Category 3: With polymyoclonus and epilepsy (the juvenile form of ceroid lipofuscinosis (Spielmeyer-Vogt or Batten disease due to CLN3gene mutations), Lafora disease, Gaucher disease type III, late onset GM-2 gangliosidosis, Niemann-Pick disease type C and respiratory chain disorders).
- Category 4: With predominant cerebellar ataxia (Friedreich ataxia, abetalipoproteinaemia and ataxia telangiectasia, peroxisomal disorders, CDG, Refsum disease and PHARC syndrome, Lafora disease, cerebrotendinous xanthomatosis, late-onset forms of gangliosidosis, Krabbe disease, Gau cher disease, Niemann-Pick disease type C and metachromatic leukodystrophy, respiratory chain disorders).
- Category 5: With predominant polyneuropathy (porphyrias and tyrosinaemia type I, lysosomal diseases (Krabbe disease, metachromatic leukodystrophy, -mannosidase), peroxisomal disorders (peroxin 7, other peroxisomal biogenesis defects, Refsum disease with demyelination and reduced nerve conduction velocities), defects of energy metabolism (Leigh syndrome, respiratory chain disorders, PDH deficiency, LCHAD and trifunctional enzyme deficiencies), abetalipoproteinaemia, CDG and a variant form of Menkes).
- Category 6: With behavioural disturbances as the presenting signs (behavioural disturbances (personality and character changes), loss of speech,scholastic failure, mental regression, dementia, psychosis and schizophrenia-like syndrome are the most frequent symptoms that occur in such dis eases as: OTC deficiency, homocystinuria, CTX, Wilson disease) [4].
Clinical manifestations of inborn errors of metabolism are nonspecific and polymorphous.
- psychomotor retardation grow up to 2 years (100%). being associated with seizure syndrome (78.9%, according to researches) and cerebral palsy (92.6%);
- seizure syndrome: in the neonatal period is caused by aciduria, hyperammonemia, methylmalonic acidemia. Grand mal seizures are caused by citrulinemie, hiperornitinemie, hyperammonemia in children up to a year;
- vomiting is most often caused by citrulinemia, hyperammonemia type I and II, hyperglycinemia, hyperlysinemia, hypervalinemia;
- metabolic acidosis is a manifestation of disturbed methionine and methylmalonic acid metabolism;
- ataxia is caused by hyperglycinemia and tryptophanuria;
- extrapyramidal syndrome occurs in the semiology of PKU and citrulinemia;
- hearing impairment occurs in hyperprolinemia and vision impairment in Low syndrome;
- hepatosplenomegaly isa consequence of aciduria;
- eczema, increased photosensitivity occur in tryptophanuria;
- specific disorders with characteristic urine odorare caused by isovaleric acidemia, phenylketonuria, methionine malabsorption.
Neurological examination of the newborn and infant has common features in the first 4-6 months of life. It is a complex and difficult one. The particular difficulties consist in the specific features of the brain, that has a still incomplete physiological maturation at this age. That’s why there are no sepcific neurological symptoms.
Main neurological symptoms are: abnormal tone with or without a motor deficit, abnormal intercourse (which is estimated by visual behavior and response to stimuli), the presence or absence of paroxysmal convulsive phenomena.
An undeniable value in newborns and infants during the first 4 months (due to poverty data obtained through neurologic examination) has the anamnesis and extraneurologic signs [1].
Acute encephalopathy occurs in newborn (diseases of small molecules) with recurrent vomiting, lethargy, anorexia, dehydration, abnormal muscle tone (hypoor hypertonia), seizures, visual disturbances, abnormal breathing, impaired consciousness, coma and death. It affects gray matter initially. It is a “poisoning” or toxic encephalopathy has a rapidly progressive evolution [8].
Chronic or progressive encephalopathy occurs in the early period, in school children and adolescents by: insidious onset, spasticity and hyperreflexia, ataxia, progressive dementia, impaired vision and hearing, liver, heart, kidney, muscle impairment caused by the disease of large molecules (or storage, hoarding). It predominantly affects white matter initially. It is a “poisoning” or energy shortage [8].
Laboratory investigations should always be performed in conjunction with clinical observations, in order to confirm or verify the hypothesis of clinical diagnosis. Less commonly, they allow diagnosis with out cilincal examination. When clinical examination reveales a mental deficiency associated with dysmorfic features and / or malformative conditions, genetic tests become necessary. Clinical examination allows selection of proper cytogenetic or molecular tests best suited to the suspected diagnosis.
What we should do when we suspect an inherited metabolic disease?
- monitoring of epileptic seizures that are not common to some or other metabolic disorders is needed. The EEG doesn’t record the paroxysmal phenomena all the time;
- it is important to track other symptoms and syndromes in order to confirm the suspected diagnosis;
- in some cases other methods of investigation may be of major importance.
The diagnosis of cerebral palsy is made from the age of 6 months. In the first months (4-6 months) there are only tone disorders. At this age the causes of hypotonia associated with paralysis of peripheral origin (spinal amyotrophy, mainly) and congenital myopathies can be easier recognized.
Suggestive signs of metabolic disorders are: proximal amyotrophy, swallowing disorders, axial hypotonia of limbs, abnormal reflexes, impaired breathing (impaired intercostal muscles and diaphragm), heart disease, hepatomegaly.
Psychomotor deficit is the most frequently encountered manifestation in metabolic or degenerative diseases. Psychomotor deficit is sometimes difficult to be confirmed when it’s onset or aggravation occurs slowly. Age of the onset, the presence of neurological signs and prevalent extraneurologic manifestations, complemented by some additional tests allow the suspicion of a plenty of metabolic or degenerative diseases .
Diagnosis of inherited metabolic diseases by the age of 1 year.
Progressive maturation of the CNS allows specific neurological signs of dysfunction of a specific region of the CNS or PNS to be revealed. The common causes of examining the child after the age of 1 year are movment disorders: delayed walking, abnormal gait, walking regression. The circumstances under which gait disorders occure, neurological symptoms and associated extraneurologic once, the use of additional tests, required with discernment, allow to work out a diagnosis, what is often easier to be done at this age.
Gait disorders are due to a motor deficit. There can be an acute or chronic and progressive onset.
Ataxia may occur in many degenerative diseases. Ataxia may be: acute they are suggestive for the following conditions: hypoglycemia, hyponatremia, hyperammonemia, Leigh disease, Wernicke encephalopathy; transient: in hypoglycemia, hyperamoniemia, abnormal organic acids, Hartnup disease, hyperpyruvic acidemia, intermittent form of leucinosis, Refsum disease, porphyria; and chronic: in degenerative diseases, Roussy-Levy disease, Wilson disease, Refsum disease, deficiency of gamma-glutamyl-cysteine synthetase, Chediak-Higashi syndrome [5].
Seizures, epilepsies and epileptic syndromes with onset after the age of 1 year.
In clinical syndromes associated with congenital lactic acidosis the differential diagnosis should be done with other inherited neurometabolic abnormalities: urea cycle abnormalities, organic aciduria, abnormalities of fatty acid oxidation, biotin-depend ent enzyme abnormalities. Determination of urinary organic acids is useful in such cases [2].
The ratio lactate / pyruvate in the blood is also needed [3].
- it is required to be excluded other conditions with elevated levels of lactic acid, such as;
- toxic medications (antibiotics: tetracycline, nalidixic acid, isoniazid; analgesics: salicylates, acetaminophen; cardiovascular: papaverine, nitroprusidat epinephrine, salbutamol, alcohols, solvents, etc.);
- systemic diseases: hypoxia, shock, respiratory alkalosis, liver failure, renal failure, diabetes, seizures and various causes of excessive muscle contracture, neoplasms.
Mitochondrial cytopathies have their onset at different ages, evolving variedly and are often critical. The most common clinical symptoms are brain manifestations, often associated with epilepsy. During the newborn period of life and in early childhood epilepsy is found in 20-60% of mitochondrial disorders. The clinical signs are grouped in well individualized syndromes as: myopathies with external ophthalmoplegia, Kearns-Sayre syndrome, Leigh syndrome, MELAS syndrome and MARRF. Epilepsy is a disorder with early onset and retarded psychomotor development, which meets less frequently in mild forms. The presence of white inclusions in MRI is one of its feature. All seizures have clinical expression. A mito chondrial cytopathy must be raised in the presence of unexplained combination of signs that involve many organs that do not have the same embryological origin.
CONCLUSIONS
Inherited metabolic diseases in children are the most complex problems to be dealt with in neuropadiatrics, althouth these are rare. The complexity arises from the clinical syndromes as well as the increasing multitude of identified biochemical defects. Specific defects can lead to a wide spectrum of clinical mani festations with onset at variable ages. Sophisticated biochemical and molecular assays are needed for a precise diagnosis in many cases.
The consideration of historical data, family history with the family tree, the notion of consanguinity, pathology related to sex and family, the concept of sudden infant death, the presence of unexplained neonatal deaths, psychomotor retardation and other neurological signs are suggestive of the assumption the diagnosis of inherited metabolic disease.
Clinical syndromes are complex and derive from the growing multitude of biochemical defects identified. Specific defects can lead to a broad spectrum of clinical signs that can have their onset at different ages. Sophisticated biochemical and molecular tests are required in many cases for accurate diagnosis.
Epileptic syndrome is often a common feature in inherited metabolic disorders.
Metabolic abnormalities should be suspected when epilepsy is resistant to antiepileptic treatment and is associated with symptoms such as: mental retardation and motor disorders.
Diagnostic methods are used depending on the age of the child. Basic examinations of metabolism include: analysis of plasma and CSF glucose, lactate level, ammonium, amino acids in plasma and CSF, level assessment of uric acid etc..
In some cases the imaging results are pathognomonic only for some metabolic disorders (eg. MRI picture is peculiar in mitochondrial citopathies).
Early diagnosis of congenital metabolic abnormalities in patients with epileptic seizures allows to select the proper treatment and thus, child’s condition improvement.
Confirmation of the diagnosis allows us to con sider measures to improve the prognosis of the disease and children’s life quality.
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