Diagnosis requires a neurological examination and neuroimaging can be helpful.

BVVL can be differentially diagnosed from similar conditions like Fazio-Londe syndrome and amyotrophic lateral sclerosis, in that those two conditions don't involve sensorineural hearing loss, while BVVL, Madras motor neuron disease, Nathalie syndrome, and Boltshauser syndrome do. Nathalie syndrome does not involve lower cranial nerve symptoms, so it can be excluded if those are present. If there is evidence of lower motor neuron involvement, Boltshauser syndrome can be excluded. Finally, if there is a family history of the condition, then BVVL is more likely than MMND, as MMND tends to be sporadic.

Genetic testing is able to identify genetic mutations underying BVVL.

Diagnosis requires a neurological examination. A neuroimaging exam can also be helpful for diagnosis. For example, an MRI can be used to discover the atrophy of the specific brain regions.

MMND can be differentially diagnosed from similar conditions like Fazio-Londe syndrome and amyotrophic lateral sclerosis, in that those two conditions don't involve sensorineural hearing loss, while MMND, Brown-Vialetto-Van Laere syndrome (BVVLS), Nathalie syndrome, and Boltshauser syndrome do. Nathalie syndrome does not involve lower cranial nerve symptoms, so it can be excluded if those are present. If there is evidence of lower motor neuron involvement, Boltshauser syndrome can be excluded. Finally, if there is a family history of the condition, then BVVLS is more likely, as MMND tends to be sporadic.

Because symptoms of ALS can be similar to those of a wide variety of other, more treatable diseases or disorders, appropriate tests must be conducted to exclude the possibility of other conditions. One of these tests is electromyography (EMG), a special recording technique that detects electrical activity in muscles. Certain EMG findings can support the diagnosis of ALS. Another common test measures nerve conduction velocity (NCV). Specific abnormalities in the NCV results may suggest, for example, that the person has a form of peripheral neuropathy (damage to peripheral nerves) or myopathy (muscle disease) rather than ALS. While a magnetic resonance imaging (MRI) is often normal in people with early stage ALS, it can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, multiple sclerosis, a herniated disk in the neck, syringomyelia, or cervical spondylosis.

Based on the person's symptoms and findings from the examination and from these tests, the physician may order tests on blood and urine samples to eliminate the possibility of other diseases, as well as routine laboratory tests. In some cases, for example, if a physician suspects the person may have a myopathy rather than ALS, a muscle biopsy may be performed.

Viral infectious diseases such as human immunodeficiency virus (HIV), human T-cell leukemia virus (HTLV), Lyme disease, syphilis and tick-borne encephalitis can in some cases cause ALS-like symptoms. Neurological disorders such as multiple sclerosis, post-polio syndrome, multifocal motor neuropathy, CIDP, spinal muscular atrophy, and spinal and bulbar muscular atrophy can also mimic certain aspects of the disease and should be considered.

ALS must be differentiated from the "ALS mimic syndromes" which are unrelated disorders that may have a similar presentation and clinical features to ALS or its variants. Because of the prognosis carried by this diagnosis and the variety of diseases or disorders that can resemble ALS in the early stages of the disease, people with ALS symptoms should always obtain a specialist neurological opinion in order to rule out alternative diagnoses. Myasthenic syndrome, also known as Lambert–Eaton syndrome, can mimic ALS, and its initial presentation can be similar to that of myasthenia gravis (MG), a treatable autoimmune disease sometimes mistaken for ALS.

Benign fasciculation syndrome is another condition that mimics some of the early symptoms of ALS but is accompanied by normal EMG readings and no major disablement.

Most cases of ALS, however, are correctly diagnosed, with the error rate of diagnosis in large ALS clinics is less than 10%. One study examined 190 people who met the MND/ALS diagnostic criteria, complemented with laboratory research in compliance with both research protocols and regular monitoring. Thirty of these people (16%) had their diagnosis completely changed during the clinical observation development period. In the same study, three people had a false negative diagnosis of MG, which can mimic ALS and other neurological disorders, leading to a delay in diagnosis and treatment. MG is eminently treatable; ALS is not.

Diagnostic procedures that may reveal muscular disorders include direct clinical observations. This usually starts with the observation of bulk, possible atrophy or loss of muscle tone. Neuromuscular disease can also be diagnosed by testing the levels of various chemicals and antigens in the blood, and using electrodiagnostic medicine tests including electromyography (measuring electrical activity in muscles) and nerve conduction studies.

In neuromuscular disease evaluation, it is important to perform musculoskeletal and neurologic examinations. Genetic testing is an important part of diagnosing inherited neuromuscular conditions.

No test can provide a definite diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb is strongly suggestive. Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the person and a series of tests to rule out other diseases. Physicians obtain the person's full medical history and usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity are worsening.

Along with evaluation of the symptoms and a neurological examination, a diagnosis can be made based on genetic testing. Whether or not a person is making sufficient amounts of functional glycogen branching enzyme can be determined by taking a skin biopsy and testing for activity of the enzyme. Examination of tissue biopsied from the sural nerve under a microscope can reveal the presence of polyglucosan bodies. There will also be white matter changes visible in a magnetic resonance imaging scans.

APBD can only be prevented if parents undergo genetic screening to understand their risk of producing a child with the condition; if in vitro fertilization is used, then preimplantation genetic diagnosis can be done to identify fertilized eggs that do not carry two copies of mutated "GBE1".

The diagnosis for DMSA1 is usually masked by a diagnosis for a respiratory disorder. In infants, DMSAI is usually the cause of acute respiratory insufficiency in the first 6 months of life. The respiratory distress should be confirmed as diaphragmatic palsy by fluoroscopy or by electromyography. Although the patient may have a variety of other symptoms the diaphragmatic palsy confirmed by fluoroscopy or other means is the main criteria for diagnosis. This is usually confirmed with genetic testing looking for mutations in the "IGHMBP2" gene.

The patient can be misdiagnosed if the respiratory distress is mistaken for a severe respiratory infection or DMSA1 can be mistaken for SMA1 because their symptoms are so similar but the genes which are affected are different. This is why genetic testing is necessary to confirm the diagnosis of DMSA.

The most useful information for accurate diagnosis is the symptoms and weakness pattern. If the quadriceps are spared but the hamstrings and iliopsoas are severely affected in a person between ages of 20 - 40, it is very likely HIBM will be at the top of the differential diagnosis. The doctor may order any or all of the following tests to ascertain if a person has IBM2:

- Blood test for serum Creatine Kinase (CK or CPK);

- Nerve Conduction Study (NCS) / Electomyography (EMG);

- Muscle Biopsy;

- Magnetic Resonance Imaging (MRI) or Computer Tomography (CT) Scan to determine true sparing of quadriceps;

- Blood Test or Buccal swab for genetic testing;

Like ALS, diagnosing PLS is a diagnosis of exclusion, as there is no one test that can confirm a diagnosis of PLS. The Pringle Criteria, proposed by Pringle et al, provides a guideline of nine points that, if confirmed, can suggest a diagnosis of PLS. Due to the fact that a person with ALS may initially present with only upper motor neuron symptoms, indicative of PLS, one key aspect of the Pringle Criteria is requiring a minimum of three years between symptom onset and symptom diagnosis. When these criteria are met, a diagnosis of PLS is highly likely. Other aspects of Pringle Criteria include normal EMG findings, thereby ruling out lower motor neuron involvement that is indicative of ALS, and absence of family history for Hereditary Spastic Paraplegia (HSP) and ALS. Imaging studies to rule out structural or demyelinating lesions may be done as well. Hoffman's sign and Babinski reflex may be present and indicative of upper motor neuron damage.

People with MMND become progressively more weak with time. Generally, affected individuals survive up to 30 years after they are diagnosed.

Treatment of ALS2-related disorders includes physical therapy and occupational therapy to promote mobility and independence and use of computer technologies and devices to facilitate writing and voice communication.

The clinical course of BVVL can vary from one patient to another. There have been cases with progressive deterioration, deterioration followed by periods of stabilization, and deterioration with abrupt periods of increasing severity.

The syndrome has previously been considered to have a high mortality rate but the initial response of most patients to the Riboflavin protocol are very encouraging and seem to indicate a significantly improved life expectancy could be achievable. There are three documented cases of BVVL where the patient died within the first five years of the disease. On the contrary, most patients have survived more than 10 years after the onset of their first symptom, and several cases have survived 20–30 years after the onset of their first symptom.

Families with multiple cases of BVVL and, more generally, multiple cases of infantile progressive bulbar palsy can show variability in age of disease onset and survival. Dipti and Childs described such a situation in which a family had five children that had Infantile PBP. In this family, three siblings showed sensorineural deafness and other symptoms of BVVL at an older age. The other two siblings showed symptoms of Fazio-Londe disease and died before the age of two.

In order to qualify a patient's condition as BSS, the bending angle must be greater than 45 degrees. While the presence of the condition is very easy to note, the cause of the condition is much more difficult to discern. Conditions not considered to be BSS include vertebral fractures, previously existing conditions, and ankylosing spondylitis. Lower-back CT scans and MRIs can typically be used to visualize the cause of the disease. Further identification of the cause can be done by histochemical or cellular analysis of muscle biopsy.

Camptocormia is becoming progressively found in patients with Parkinson's disease.

The diagnosis of Parkinson's-associated camptocormia includes the use of imaging of the brain and the spinal cord, along with electromyography or muscle biopsies.

Muscle biopsies are also a useful tool to diagnose camptocormia. Muscle biopsies found to have variable muscle fiber sizes and even endomysial fibrosis may be markers of bent spine syndrome. In addition, disorganized internal architecture and little necrosis or regeneration is a marker of camptocormia.

Patients with camptocormia present with reduced strength and stooped posture when standing due to weakened paraspinous muscles (muscles parallel to the spine). Clinically, limb muscles show fatigue with repetitive movements. Paraspinous muscles undergo fat infiltration. Electromyography may be used as well in diagnosis. On average, the paraspinous muscles of affected individuals were found to be 75% myopathic, while limb muscles were 50% percent myopathic. Creatine kinase activity levels in skeletal muscle are a diagnostic indicator that can be identifiable through blood tests.

In terms of treatment for neuromuscular diseases (NMD), "exercise" might be a way of managing them, as NMD individuals would gain muscle strength. In a study aimed at results of exercise, in muscular dystrophy and Charcot-Marie-Tooth disease, the later benefited while the former did not show benefit; therefore, it depends on the disease Other management routes for NMD should be based on medicinal and surgical procedures, again depending on the underlying cause.

The importance of correctly recognizing progressive muscular atrophy as opposed to ALS is important for several reasons.

- 1) the prognosis is a little better. A recent study found the 5-year survival rate in PMA to be 33% (vs 20% in ALS) and the 10-year survival rate to be 12% (vs 6% in ALS).

- 2) Patients with PMA do not suffer from the cognitive change identified in certain groups of patients with MND.

- 3) Because PMA patients do not have UMN signs, they usually do not meet the "World Federation of Neurology El Escorial Research Criteria" for “Definite” or “Probable” ALS and so are ineligible to participate in the majority of clinical research trials such as drugs trials or brain scans.

- 4) Because of its rarity (even compared to ALS) and confusion about the condition, some insurance policies or local healthcare policies may not recognize PMA as being the life-changing illness that it is. In cases where being classified as being PMA rather than ALS is likely to restrict access to services, it may be preferable to be diagnosed as "slowly progressive ALS" or "lower motor neuron predominant" ALS.

An initial diagnosis of PMA could turn out to be slowly progressive ALS many years later, sometimes even decades after the initial diagnosis. The occurrence of upper motor neurone symptoms such as brisk reflexes, spasticity, or a Babinski sign would indicate a progression to ALS; the correct diagnosis is also occasionally made on autopsy.

Diagnosis is clinical and initially consists of ruling out more common conditions, disorders, and diseases, and usually begins at the general practitioner level. A doctor may conduct a basic neurological exam, including coordination, strength, reflexes, sensation, etc. A doctor may also run a series of tests that include blood work and MRIs.

From there, a patient is likely to be referred to a neurologist or a neuromuscular specialist. The neurologist or specialist may run a series of more specialized tests, including needle electromyography EMG/ and nerve conduction studies (NCS) (these are the most important tests), chest CT (to rule out paraneoplastic) and specific blood work looking for voltage-gated potassium channel antibodies, acetylcholine receptor antibody, and serum immunofixation, TSH, ANA ESR, EEG etc. Neuromyotonia is characterized electromyographically by doublet, triplet or multiplet single unit discharges that have a high, irregular intraburst frequency. Fibrillation potentials and fasciculations are often also present with electromyography.

Because the condition is so rare, it can often be years before a correct diagnosis is made.

NMT is not fatal and many of the symptoms can be controlled. However, because NMT mimics some symptoms of motor neuron disease (ALS) and other more severe diseases, which may be fatal, there can often be significant anxiety until a diagnosis is made. In some rare cases, acquired neuromyotonia has been misdiagnosed as amyotrophic lateral sclerosis (ALS) particularly if fasciculations may be evident in the absence of other clinical features of ALS. However, fasciculations are rarely the first sign of ALS as the hallmark sign is weakness. Similarly, multiple sclerosis has been the initial misdiagnosis in some NMT patients. In order to get an accurate diagnosis see a trained neuromuscular specialist.

PMA is a diagnosis of exclusion, there is no specific test which can conclusively establish whether a patient has the condition. Instead, a number of other possibilities have to be ruled out, such as multifocal motor neuropathy or spinal muscular atrophy. Tests used in the diagnostic process include MRI, clinical examination, and EMG. EMG tests in patients who do have PMA usually show denervation (neurone death) in most affected body parts, and in some unaffected parts too.

It typically takes longer to be diagnosed with PMA than ALS, an average of 20 months for PMA vs 15 months in ALS/MND.

DSMA1 is usually fatal in early childhood. The patient, normally a child, suffers a progressive degradation of the respiratory system until respiratory failure. There is no consensus on the life expectancy in DSMA1 despite a number of studies being conducted. A small number of patients survive past two years of age but they lack signs of diaphragmatic paralysis or their breathing is dependent on a ventilation system.

Lafora Disease is diagnosed by doing a series of tests by a neurologist, epileptologist (person who specializes in epilepsy), or geneticist. To confirm the diagnosis, an EEG, MRI, and genetic testing are needed to detect the activity of the brain and potential genetic relation to Lafora Disease. A biopsy may be necessary as well to detect and confirm the presence of Lafora bodies in the skin. Typically, if a patient comes to a doctor and has been having seizures, like patients with LD characteristically have, these are the common tests that would happen right away to figure out areas of the brain where the seizures are occurring. Whole genome or exome testing is necessary to have with anyone who suffers from epilepsy.

Clinical studies have revealed that camptocormia may be hereditary; however, the inheritance mechanism remains unclear. Current areas of research include molecular and genetic studies aimed at elucidating a possible inheritance model along with molecular pathological mechanisms and proteins responsible for BSS. This research will help will facilitate improvement in the classification, diagnosis, and treatment of the condition. In addition, new technologies and animal models of postural abnormalities are being developed to understand camptocormia and design more effective treatment methods.

The confirmatory diagnosis is made via brain biopsy, however, other tests can be used to help such as MRI, EEG, CT, as well as the physical exam and history

A 2009 review noted that muscle weakness usually begins after age 20 and after 20–30 years, the person usually requires a wheel chair for mobility. There was no mention of increased mortality.

Benign fasciculation syndrome is a diagnosis of exclusion; that is, other potential causes for the twitching (mostly forms of neuropathy or motor neuron diseases such as ALS) must be ruled out before BFS can be assumed. An important diagnostic tool here is electromyography (EMG). Since BFS appears to cause no actual nerve damage (at least as seen on the EMG), patients will likely exhibit a completely normal EMG (or one where the only abnormality seen is fasciculations).

Another important step in diagnosing BFS is checking the patient for clinical weakness. Clinical weakness is often determined through a series of strength tests, such as observing the patient's ability to walk on his or her heels and toes. Resistance strength tests may include raising each leg, pushing forward and backward with the foot and/or toes, squeezing with fingers, spreading fingers apart, and pushing with or extending arms and/or hands. In each such test the test provider will apply resisting force and monitor for significant differences in strength abilities of opposing limbs or digits. If such differences are noted or the patient is unable to apply any resisting force, clinical weakness may be noted.

Lack of clinical weakness along with normal EMG results (or those with only fasciculations) largely eliminates more serious disorders from potential diagnosis.

Especially for younger persons who have only LMN sign fasciculations, "In the absence of weakness or abnormalities of thyroid function or electrolytes, individuals under 40 years can be reassured without resorting to electromyography (EMG) to avoid the small but highly damaging possibility of false-positives". "Equally, however, most subspecialists will recall a small number of cases, typically men in their 50s or 60s, in whom the latency from presentation with apparently benign fasciculations to weakness (and then clear MND) was several years. Our impression is that a clue may be that the fasciculations of MND are often abrupt and widespread at onset in an individual previously unaffected by fasciculations in youth. The site of the fasciculations, for example, those in the calves versus abdomen, has not been shown to be discriminatory for a benign disorder. There is conflicting evidence as to whether the character of fasciculations differs neurophysiologically in MND".

Another abnormality commonly found upon clinical examination is a brisk reflex action known as "hyperreflexia". Standard laboratory tests are unremarkable. According to neurologist John C. Kincaid:

Neuromyotonia is a type of peripheral nerve hyperexcitability. Peripheral nerve hyperexcitability is an umbrella diagnosis that includes (in order of severity of symptoms from least severe to most severe) benign fasciculation syndrome, cramp fasciculation syndrome, and neuromyotonia. Some doctors will only give the diagnosis of peripheral nerve hyperexcitability as the differences between the three are largely a matter of the severity of the symptoms and can be subjective. However, some objective EMG criteria have been established to help distinguish between the three.

Moreover, the generic use of the term "peripheral nerve hyperexcitability syndromes" to describe the aforementioned conditions is recommended and endorsed by several prominent researchers and practitioners in the field.