SPINAL MUSCULAR ATROPHI CLASIFICATION, CLINICAL AND LABORATORY FEATURES
Spinal Muscular Atrophy (SMA) refers to a disorder characterized by muscular atrophy secondary to degeneration of the spinal motor neurons. Although there are many progress in the field of recessive SMA with molecular defects on chromosome 5 (SMA 5q), in the non5q entities molecular diagnosis and the phenotypic spectrum are still not well known. The types I, II, III of proximal recessive SMA of the child are characterized by the age of onset, motor function achieved and age of death. These are the result of mutations on SMN gene in the 5q region of the 5 chromosome. Other types of SMA (SMA plus) characterized by atypical clinical signs were defined as separate entities, with different molecular mutations. Now, the diagnosis is confirmed by finding the mutation on the SMN gene. Spinal Muscular Atrophies 5q are the most frequent degenerative diseases of the nervous central system, on the second place (after Duchenne Muscular Distrophy), one of the most important genetic causes of disabilities and infantile death.
The term spinal muscular atrophy (SMA) implies a condition involving muscle atrophy secondary to the damage of the spinal motoneuron. Taken in this sense, it includes a large number of heterogeneous clinical syndromes, most of them, but not all, being transmitted genetically. Given the recent progress in molecular medicine, the term spinal muscular atrophy or spinal amyotrophy came to have two separate meanings: one for a specific monogenic disease and another as the descriptive term for a group of alleged genetic diseases of the motor neuron. As a precise term, spinal muscular atrophy (SMA) is used for diseases caused by mutations in the SMN gene (on chromosome 5). As a generic term, it applies to quite diverse affections, some of them better, others less well characterized, where the degeneration of motor neurons of the spinal cord and of the brainstem is the predominant feature (3). This article provides data on SMA caused by mutations in the SMN gene.
Classification encounters numerous difficulties, as spinal muscular atrophy is a clinically variable and genetically heterogeneous disorder. Although substantial progress has been made in research on recessive SMAs localized on chromosome 5 (5q SMA), there are currently very limited data available in relation to non-5q entities in terms of molecular diagnosis and phenotype frequencies. The possibility to analyze the SMN gene allowed the delineation of the “classic”, proximal diagnostic criteria of SMA and their clinical variability. On the other hand, various SMA entities of can be defined as having atypical features that are not caused by mutations on chromosome 5q. Thus, areas of interest are currently focused on the discovery of other genes responsible for the degeneration of the anterior horn cells. Based on the clinical description of the transmission pattern, some authors have developed a classification that includes clinically recognised syndromes with several known genetic mutations. However, there is a large number of syndromes with uncertain nosology that have not been included (18) (Table 1).
Classification of 5q SMAs (connected to chromosome 5)
Classic types I, II, III of proximal recessive SMAs in children are defined in terms of age of onset and severity of symptoms and will be detailed below. These are caused by deletions or mutations in the SMN (survival motor neuron) gene in the SMA 5q region. Recently, other forms of SMA (“SMA plus” types) characterized by atypical clinical signs have been defined as separate entities. The types of “SMA plus” appear to have other genetic mutations unrelated to the region 5q13 (23).
Attempts to achieve a single classification based on age of onset, pattern of transmission and the distribution of the muscular deficit has led to overlapping. Although SMAs are classified into three subtypes (not including subtype IV which is the adult form), their clinical course is variable and rather a continuum spectrum with: age of onset from birth to adulthood, the age of death spanning from infancy to adulthood and even a variable range of progression, depending on the respiratory function and on the potential for ventilatory support (20).
In 1992, the International SMA Consortium adopted well-defined ages of onset and death as classification criteria:
SMA type I (severe):
-onset from birth to 6 months,
-death usually around age 2 years.
SMA type II (intermediate)
-onset at the age of 18 months
-death after the age of 2 years
SMA type III (mild)
-debut over 18 months of age
-death in adulthood
Table 1. Classification of spinal muscular atrophies (18)
In 1999, the International SMA Consortium adopted a major revision of diagnostic criteria, where the motor acquisitions were included as an important classification criterion (22).
Because of this revision, the following were included:
-SMA type I – patients can not sits without support,
-SMA type II – patients can sits without support, but can not walk without support,
-SMA type III patients can walk without support,
-SMA type IIIa – debut at 3 years old,
-SMA type III b – debut at ages from 3 to 30 years,
-SMA type IV – patients’ debut around the age of 30 years.
Given the new clinical studies and case reports, another type of SMA has been proposed – antenatal SMA type or form. Today we may speak of the following clinical types of SMAs that have mutations on chromosome 5 (see Table 2) (17).
Type 0 (prenatal form)
-extended muscle deficit
-swallowing disorders, respiratory disorders
-possible facial diplegia, ophthalmoplegia
-no motor acquisitions
-death occurs is not the first 3 months of life
Type I (severe infantile form, Werdnig Hoffmann)
-debut in the first quarter of life
-does not acquire sitting position
-can support the head
Type II (intermediate form)
-onset in the first quarter
-allows the initial acquisition of sitting
-Can sit in upright position, but does not acquire walking
Type III (mild form, Wohlfart-Kugelberg-Welander)
-3a onset age < 3 years (18 months -3 years)
-3b onset age> 3 years (3-30 years)
Type IV (adult form)
AUTOSOMAL RECESSIVE SPINAL MUSCULAR ATROPHZ 5Q
Spinal amyotrophies related to mutations on chromosome 5 are the most common degenerative diseases of the central nervous system, being the second most common inherited neuromuscular disease after Duchenne type of progressive muscular dystrophy and therefore one of the most important genetic causes of infant death and disability.
The incidence in the population for all three types (I-III) of autosomal recessive SMA was measured consistently and the value of 1/6000-10.000 live babies was found (which can go up to 1/25.000) (19). A number of population studies suggest that, in Réunion Island and in Karaite community in Israel, they can be isolated genetically and that SMA may have a different genetic basis in black people from South Africa (18).
Table 2. Types of SMAs 5q (17)
5q recessive SMA was first described in 1890 by Guido Werdnig, a doctor in Vienna, in his lecture “On a Case of Muscular Dystrophy with Positive Spinal Cord Findings.” Soon afterwards, Professor Johann Hoffmann from Heidelberg University, presented a paper describing the syndrome of progressive atrophy, muscle deficit and early death in childhood, with genetically normal parents. The two scientists have carried out biopsies on their patients and found severe atrophy of the earlier roots of the spinal cord. They also found histological signs suggestive of motoneuron loss in the previous horn cells of this region. Hoffman syndrome called “spinal muscular atrophy (19).
In 1960s, in an effort to evaluate the prognosis, Byers and Banker classified SMAs into categories based on the severity of symptoms and on the onset age. Their system became the basis for the most recognized classification system currently used for classifying the SMA (14). In 1955 and 1956, Wohfart Kugelberg and Welander identified the form with onset between 18 months and 17 years, Spinal Muscular Atrophy type III.
Taking into consideration that laboratory examinations are the same for all types while the clinical aspects are different, I will start with the describtion of different types of SMAs in terms of clinical manifestations, and I will describe the laboratory examinations later.
Types of 5q spinal muscular atrophy SMA Type 0 (prenatal)
Incidence at birth is rare and the diagnostic criteria for SMA do not include antenatal presentation in the 1999 classification proposed by the “European Neuromuscular Centre” (ENMC), although cases have been reported with onset in utero (11).
In terms of classification, the most severe cases of SMA, with prenatal onset and intrauterine death or with severe birth asphyxia and early neonatal death may be included in a category of “very severe” SMA (type 0) as a variant of the type of severe SMA (i.e. of type I) (5, 11).
New babies have major, global, paralytic, hypotonia, and areflexia. Antenatal onset may lead to the existence of joint retractions (equine foot, elbow bent, fingers and knees without a real change in the axis, usually reducible by mobilizing physiotherapy); they have nothing to do with arthrogryposis appearing in other neonatal neuropathies. During pregnancy, fetal movements are reduced, and the cry is weak after birth. Usually patients have respiratory insufficiency and sucking deficiency and swallowing disorders cause the necessity of gavage. New babies who are hypotone both in utero and at birth may have difficulties adapting to life outside the womb and have postnatal asphyxia and encephalopathy. Some of them are dependent on ventilatory support. They may display facial diplegia and disorders in ocular motricity. Death occurs in the first 3 months of life.
Although arthrogryposis is considered to be an exclusion criterion in SMA, Bingham et al have reported two infants with multiple joint contractures that had 5q deletion (1).
A hypotonic newborn patient was described in specialist literature with multiple joint contractures, multiple fractures and respiratory failure, which had homozygous deletion of SMN1 gene and one single copy of SMN2. These cases show that the presence of atypical symptoms in the neonatal period should not preclude a form of SMA 5q (6).
Spinal muscular atrophy Type I (Werdnig-Hoffmann disease)
It is a disease with onset before the age of 6 months (under the age of 3 months), by decreasing motility at the proximal level of the limbs, much stronger at the level of the lower limbs. The deficit becomes generalized in a few weeks, thus there is a symmetric flaccid quadriparesis, too. Facial muscles and ocular motricity are not affected.
The baby has an aspect of a “floppy baby”, caused by the damage, to a lesser extent, of the distal region of the limbs, which allow distal movement of the toes and fingers and even of the forearms, while the major proximal damage is affecting the limb roots allowing them to rest on the bed, with thighs in flexion-abduction- external rotation, knees in the semi-flexion, the equine foot, arms in internal rotation, elbows bent, forearms in forced pronation, fists in extension, the fingers flexed (“frog-like position”). The paralysis of intercostals muscles is common and constant, the baby breathes only with the diaphragm, which causes a paradoxical depression in the chest during inspiration while the belly expands (paradoxical breathing). Crying is short and without force, and the cough is ineffective.
Osteo-tendon reflexes are abolished early in the disease, helping to differentiate from other causes of central hypotonic syndrome.
Fasciculations at tongue level are present in most but not in all patients. . Postural tremor was described at fingers level, too.
Swallowing disorders occur quite late, there are no sphincter or sensitivity disturbances (15). Often, atrophies are not so evident in SMA type I, because there is a tendency for compensatory proliferation of the subcutaneous tissue.
Cognitive functions are normal and are certified by the lively look and the normal mental acquisitions.
Spinal muscular atrophy Type II
It is the most common form of SMA, some experts arguing that it can overlap with type I or III (19).
Onset is usually between 6 and 12 months of life. Although the decreased muscle tone may be present since birth or since the first months of life, patients with SMA type II may develop motor acquisitions slowly. Evolution is insidious; the reason for coming to the doctor is the absence of motor acquisitions rather than their regress:
-most often the reason is the inability to take the seating position or to walk up to the age of one year;
-sometimes, it is the absence of the acquisition of gait, when sitting position and orthostatic position with support have already been acquired at the normal age;
-more rarely, complete stagnation of motor progress following the acquisition of head maintaining at the normal age;
At diagnosis, the spontaneous attitude in dorsal decubitus is identical to that of type I, due to hypotonia, but the deficit is less intense (see Figure 1).
Usually, the baby can sit with the torso bent forward forming a gibbosity and often a tripod support while the thighs remain flaccid in abduction-external rotation on the plane of the bed; the pelvic deficiency usually does not allow body weight support, the upper limbs maintain a variable motility allowing the use of hands for habitual activities (leading objects to mouth, but it rarely raises his arms above his head).
The maximum motor acquisition achieved is the independent sitting ability. The rotulian osteo-tendon reflexes (OTR) are always abolished, the Achillean and upper limb OTRs can be preserved, but they disappear afterwards. Swallowing is normal. Fasciculations of the tongue are not a striking feature in type I but they are present in 70% of SMA type II patients and so is the limb tremor (they are correlated with fasciculations in skeletal muscle).
Pseudohipertrofia of the gastrocnemius muscle may occur, together with skeletal deformities and respiratory insufficiency. Impaired chest is constant (Figure 2) but of variable importance: in about half of cases there is no chest deformation, the chest cage is supple and there is a certain degree of respiratory expansion.
The initial period of installation of the deficit, that usually extends over a period of 6-8 weeks, is followed by period in which the clinical picture remains stable, even allowing for the resumption of acquisitions (sitting position at 2-4 years, walking a fewstweps alone at 5 years old).
Figure 1. Infant with SMA Type II
Figure 2. Skeletal deformities (cifo-scoliosis) in a pacient with SMA type II
Spinal muscular atrophy Type III (Kugelberg– Welan-der Disease, Wohlhart-Kugelberg –
Patients with SMA type III are characterized by slowly progressive proximal muscular deficit. Patients often complain of symptoms associated with muscular deficit of the extensor and abductor muscles of the thigh and describe the difficulties when climbing the stairs or standing up from a sitting position. Some patients may describe a light and occasional tremor, painful muscle cramps, difficulty inwalking or running. Parents of the younger patients tell about a delay in motor acquisitions or about decreased sports skills of their children. Family history may be positive.
At clinical examination, patients present muscle deficit at the level of pelvic girdle, much more severe than at the scapular belt level, with positive Gowers and waddle. Approximately one third of patients may present a deficit of the facial muscles and of the masseters.
OTR are reduced (the Achillian ones may be present until later in the course of the disease). Fasciculations may be present on the tongue level or at the level of the scapular girdle muscles (especially after muscle strength testing). Minipolimioclonus may be present, a fine, irregular tremor of the fingers when the upper limbs are stretched anteriorly.
Pseudohypertrophy of the calf muscles may be present, but most obvious are the atrophies of the affected muscles. Sensitivity problems are absent.
Several studies have shown that scoliosis is a major problem in half of patients with SMA type III. However, this is less common in patients with SMA type III than in those with type II and it is not so severe. Subluxation of the hip is also common (14).
Lung diseases are a major cause of morbidity and mortality in patients with SMA type I and II but in a low proportion of patients with SMA type III (14). Patients often report daytime fatigue that can result from sleep apnea or nocturnal hypoventilation, which can be solved by using continuous non-invasive nocturnal ventilation. Contractures are usually mild as long as patients remain ambulatory.
Creatine kinases have normal values or are slightly increased. The following tests were used in the past to establish the diagnosis of SMA but now they have a less important role in the diagnosis of most patients with SMA and are used especially if molecular genetic testing of the SMN1 gene is normal.
The electromyographic characteristics of the disease show features of denervation and decreased motor action potential. Spontaneous activity of the positive sharp wave type, of fibrillation and occasionally fasciculation, occurs most frequently in SMA type I and occasionally in SMA type II, but not in SMA type III. (2.7). At maximum effort, an interferential path is obtained. Motor and sensory nerve conduction velocities (NCV) are normal. When NVC is slightly lower, it may accompany a severe axonal motor loss due to motor fibres that are fast conductors (15). Electrophysiological studies are useful in differentiating spinal muscular atrophies or other neurogenic or miogene disorders.
Histological features of the muscle depend on the stage and progression of the disease. At first, atrophies of muscle fibres appear with compensatory hypertrophy. They cause the grouping of large fibres and small fibres (fibre type grouping) (15). Hypomielinization of peripheral nerves is noted in prenatal form while in the other types, the nerve has a normal histology (9, 11).
Muscle biopsy may be necessary to distinguish spinal muscular atrophies from other neuromuscular diseases where genetic testing is not relevant. The selection of the muscle for biopsy should be based upon clinically affected muscles but their degeneration should not be so advanced as to make interpretation irrelevant. (19). Histopathologically, the spinal cord shows a severe loss of motor neurons in the anterior horn region (see Figure 3).
Figure 3. Histopathology SMA (10)
Legend: Motor commands generated in the cerebral cortex are transmitted to the alpha motor neurons of the spinal cord. The region of the anterior motor horn shows the absence of motor neurons in a patient (B) when compared to a healthy subject (A). Skeletal muscle of a patient shows hypertrophic fibers surrounded by atrophic fibres in a patient with SMA (D) compared with healthy fibers with uniform morphology (C). Despite the atrophy of muscle fibers in the SMA, muscle spindles are not affected and they become more evident (D). All slides are coloured with hematoxylin and eosin.
DIAGNOSIS . CRITERIA
The common clinical and laboratory features are (see Table 3) (12, 23)
-Muscle deficit of bilaterally symmetrical torso and limbs, with predilection for proximal muscles, with a progressive pattern;
-Fasciculation and tremor of upper limbs may be associated;
-Hand tremor is seen frequently, with features related to the type of SMA after the age of onset.
Exclusion criteria (13, 22)
-affecting extra ocular muscles, diaphragm and myocardial muscles, significant facial diparesis,
-central nervous system dysfunction,
-involvement of neurological impairment (hearing, sight),
-CK> 10 times higher compared the normal values,
-low conduction velocity <70% of the lower limit of normal values or anomalies of the sensory nerves
Considering all the above aspects, the following diagnostic algorithm has been developed (figure 4) (10):
-Any patient with clinical signs suggesting SMA has to be tested for homozygous deletion of SMN1, which may confirm the diagnosis of 5q-SMA.
-A negative test must be followed by a clinical re-assessment of the atypical features (e.g., contractures, hemi diaphragm eventration, congenital absence of certain muscles, deformations of the type equine varus) and laboratory testing for creatine kinase (CK) and electrophysiological studies (electromyography – EMG; nerve conduction velocities – NCV.)
-If these laboratory tests suggest a disease of the motor neuron, the number of SMN1 copies will determine whether the sequencing test is recommended in order to detect intragenic mutations in patients with a single copy of SMN1.
-When two SMN1 copies are present, investigations should be directed to another motor neuron disease: muscle and nerve biopsy, genetic testing for myopathy, neuropathy, imaging studies, metabolic screening tests (SMARD-SMA with respiratory distress- SMA with respiratory failure, N-normal values).
Undoubtedly, there are clear examples of borderline patients who are at the boundary of different types. In children with SMA type I, mothers occasionally describe a sudden interruption of foetal movements in the third quarter, which may suggest that in severe cases the process of motoneuron loss can begin in utero. Most cases of classic Werdnig Hoffmann disease become manifest in the first six months of life as severe muscle deficit requiring intubation at birth or the patients do not acquire head control. Key prognostic feature is that children do not acquire the ability to sit unsupported. Of those who meet this criterion, most die from respiratory failure in the first two years of life. Although there are cases that have a prolonged survival with invasive ventilatory support, non-inva sive measures such as intermittent ventilation with positive pressure did not improve the unfavourable evolution of these patients (21).
Table 3. Diagnosis criteria in SMA
Figure 4. Diagnosis algorithm for spinal muscular atrophy (10)
SMARD – SMA distal with respiratory distress; SLA – amyotrophic lateral sclerosis; EMG -electromyography;
NCS – nerve conduction velocities (studies); CK – creatinkinases
In SMA type II, affected patients acquire the ability to sit without support but they are never able to stand and therefore have a severe disability. Prognosis, which is very variable, depends largely on the degree of impairment of respiratory muscles and on associated problems caused by the development of cifoscoliosis, which, in contrast to Duchenne progressive muscular dystrophy, may occur in infancy.
Life span ranges from 2 years to the 3rd decade of life, death is the result of respiratory infections in most cases. Affected patients lose the ability to sit independently in the middle of adolescence (16, 21).
In a large number of clinical series of SMA type III, SMA is defined by unassisted walking as maximum acquisition, although ambulation is then lost in many patients. Patients with SMA type III who have never climbed stairs without support lose their ability to walk in the middle of adolescence. (16). Patients with normal motor acquisitions of walking before the emergence of the deficit can keep walking until 3rd or 4th decade of life. Life expectancy is considered normal (3).
Spinal muscular atrophies (SMA) make up a clinically and genetically heterogeneous group. In this article we have detailed the proximal recessive SMAs caused by mutations on chromosome 5 (5q SMA), at the level of SMN gene. Currently the diagnosis is confirmed by detection of mutations. If genetic testing is negative, other laboratory examinations (electrophysiological tests, muscle biopsy) are performed.
Over time, a classification of the SMAs has been attempted. At present, the one undertaken in 1999 by the International SMA Consortium is in use. It divides SMA into three types (type IV includes the adults) according to the age of onset, age of death and motor acquisitions.
Most researchers define the type of spinal amyotrophy by the highest level of motor function (ability to sit, to walk).
No doubt, there are clear examples of patients who are at the limit of various types. Attempts to provide a unique classification based on age of onset, pattern of transmission and distribution of muscular deficit has led to overlapping. Studies show that maximum of acquired function is more closely correlated with life expectancy than with the age of onset, which is important in determining patient prognosis and evolution.
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